Ferroptosis: A new horizon in cancer therapy.

Introduction
The intrinsic heterogeneity of tumors and their dynamically adaptive survival mechanisms have driven the need for innovative precision therapeutic strategies. Ferroptosis—a form of regulated cell death was first formally proposed and coined in 2012 by Dr. Scott J. Dixon and colleagues in Brent R. Stockwell’s laboratory—has garnered significant attention in recent years due to its potential to overcome tumor resistance to conventional therapies [Figure 1]. Distinct from apoptosis and necrosis, ferroptosis is initiated through the oxidation of polyunsaturated fatty acid-containing phospholipids (PUFA-PLs) and amplified by iron-mediated Fenton reactions.[1,2] Ferroptosis activates antigen-presenting cells (APCs) by releasing damage-associated molecular patterns (DAMPs) and depletes immunosuppressive cell populations,[3] fostering an immunostimulatory microenvironment, which highlights the transformative potential of combination therapeutic modalities.[4] The coupling between ferroptosis regulatory networks and tumor metabolic signatures offers novel perspectives for developing innovative therapies based on the modulation of cell death mechanisms.
This review aims to go beyond traditional descriptions of the molecular mechanisms of ferroptosis and its dichotomous roles in tumorigenesis and cancer progression by offering a more integrative and mechanistically nuanced perspective. We systematically consolidate and critically analyze the emerging synergistic interactions between ferroptosis and mainstream anticancer strategies, including chemotherapy, targeted therapy, radiotherapy, hyperthermia therapy (HTT), and immunotherapy. Particular attention is devoted to the emerging frontier of nanomaterial-mediated thermal therapies, such as photothermal therapy (PTT) and magnetic hyperthermia therapy (MHT), and their potent synergy with ferroptosis induction. We describe how functionalized nanocarriers, through precisely controlled spatiotemporal thermal effects, selectively impair tumor antioxidant defenses and disrupt iron homeostasis, such as by inhibiting glutathione peroxidase 4 (GPX4), depleting glutathione (GSH), promoting ferritinophagy, and releasing labile iron, thereby sensitizing cancer cells and amplifying ferroptotic responses. This review further elaborates on a novel ferroptosis-centered strategy for precision cancer therapy, which integrates the selective induction of tumor-specific metabolic vulnerabilities, such as iron overload and lipid peroxidation, with the remodeling of the immunosuppressive tumor microenvironment (TME) to enhance antitumor immunity, thereby aiming to overcome therapeutic resistance and eliminate refractory malignancies. By targeting cancer-specific vulnerabilities, particularly dysregulated iron metabolism and abnormal lipid peroxide metabolism, ferroptosis paves the way for a new mechanism-driven framework in cancer treatment.

Molecular Mechanism of Ferroptosis in Cancer
Ferroptosis is an iron-dependent form of regulated cell death, triggered by the peroxidation of polyunsaturated phospholipids (PUFA-PLs). It disrupts plasma membrane integrity through the activation of mechanosensitive ion channels, particularly Piezo1 and transient receptor potential channels,[5,6] ultimately leading to osmotic imbalance and catastrophic membrane rupture. The execution of ferroptosis relies on the coordinated interplay among lipid peroxidation, iron overload, and impaired antioxidant defenses. These mechanisms suggest distinct strategies in cancer therapy, such as directly inducing lipid peroxidation by inhibiting the cystine/glutamate antiporter system Xc− or depleting GPX4 to eliminate malignant cells, while simultaneously modifying iron metabolism and antioxidant adaptations in the TME to increase lipid peroxidation and reverse treatment resistance [Figure 2]. This multifaceted approach addresses the limitations of conventional therapies, particularly in refractory malignancies, by exploiting unique vulnerabilities in tumors and reshaping the immunosuppressive microenvironment, and highlights the revolutionary potential of ferroptosis in clinical oncology.

Lipid peroxidation: The ultimate executor
The oxidation of PUFA-PLs embedded in cellular membranes results in phospholipid hydroperoxide (PL-OOH), a hallmark of ferroptosis. In nonenzymatic lipid peroxidation reactions, PUFAs are susceptible to oxidation because of the comparatively weak C–H bonds between neighboring C = C double bonds. This makes the hydrogen atoms linked to carbon more likely to be replaced by peroxy radicals (O–O) generated during metabolism.[7] However, the oxidation of PUFAs alone does not directly induce cytotoxicity; it is specifically the peroxidation of PUFAs incorporated into membrane phospholipids that initiates ferroptosis. Among various PUFAs, arachidonic acid (AA) and adrenic acid are more closely associated with ferroptosis.[8] Under the catalytic action of acyl-CoA synthetase long-chain family member 4 (ACSL4), AA and adenosine deaminase (ADA) are converted into their corresponding acyl-CoA derivatives, which are subsequently esterified into phospholipids by lysophosphatidylcholine acyltransferase 3 (LPCAT3) and incorporated into the sn-2 position of membrane phospholipids. The resulting PUFA-PLs serve as the primary substrates for lipid peroxidation during ferroptosis.[9–11] This biochemical transformation is critical for the execution of ferroptosis.
Lipid peroxidation occurs through two interconnected pathways. In the first pathway, arachidonate lipoxygenases (ALOXs), particularly ALOX15 and ALOX12, directly oxygenate PUFA-PLs,[12] with the phosphatidylethanolamine-binding protein 1 (PEBP1)/ALOX15 complex generating PUFA-phosphatidylethanolamine (PUFA-PE) hydroperoxides that contribute to membrane damage.[13] In addition, cytochrome P450 oxidoreductase (POR) directly provides electrons to P450 enzymes, catalyzing the peroxidation of PUFA-PLs in an ALOX-independent manner.[14] In the second pathway, iron-catalyzed Fenton reactions produce hydroxyl radicals (·OH), which initiate a chain reaction in which lipid radicals react with oxygen to form lipid peroxyl radicals.[15,16] These radicals abstract hydrogen from adjacent PUFAs, resulting in the formation of lipid hydroperoxides and perpetuating oxidative damage to the membrane.
Ferroptosis in tumors is driven by increased lipid peroxidation and oxidative stress through coordinated metabolic rewiring. Specifically, inhibition of lysophosphatidylcholine acyltransferase 1 (LPCAT1) elevates membrane PUFA levels by reducing the phospholipid saturation,[17] thereby sensitizing cells to peroxidation. Concurrently, activation of the p53/spermidine/spermine N1-acetyltransferase 1 (SAT1)/ALOX15 axis directly promotes PUFA peroxidation.[18] Moreover, epigenetic regulation mediated by mixed-lineage leukemia 4 (MLL4), further potentiates lipid oxidation through upregulation of ALOXs, such as ALOX12, accelerating the accumulation of lipid hydroperoxides.[19] Additional mechanisms contribute to this process by promoting the transfer of PUFAs from lipid droplets to oxidation-prone membranes via phospholipid transfer proteins[20] or through targeting cyclin-dependent kinase inhibitor 2A (CDKN2A).[21] Simultaneously, inhibition of calcium-independent phospholipase A2β (iPLA2β)-mediated detoxification disrupts cellular antioxidant defenses, together synergistically amplifying lipid peroxidation cascades and driving ferroptotic cell death.[22]
Reactive oxygen species (ROS) dynamics critically regulate ferroptosis sensitivity. Arginine-derived hydrogen peroxide (H2O2) acts as an initiator of lipid peroxidation,[23] thereby facilitating ferroptotic cell death. Concurrently, impairment of the mitochondrial cyclic GMP–AMP synthase (cGAS) and dynamin-related protein 1 (DRP1) complex compromises ROS scavenging capacity, exacerbating oxidative damage.[24] Moreover, inhibition of methyltransferase-like protein 17 (METTL17) destabilizes mitochondrial RNA methylation, impairing electron transport and triggering ROS overproduction.[25] These interconnected mechanisms converge to dismantle antioxidant defenses, overriding adaptive resistance in refractory tumors through the exploitation of the redox imbalance in tumors and their metabolic vulnerability.

Iron metabolism: The catalyst of destruction
Iron serves as both a cofactor and amplifier of ferroptosis. Cellular iron uptake is mediated by transferrin receptor (TFRC)-dependent endocytosis, wherein Fe3+ is internalized and subsequently reduced to Fe2+ within endosomes. The reduced Fe2+ is then transported into the cytosol by divalent metal transporter 1 (DMT1), contributing to the labile iron pool (LIP).[26] Excess cytosolic Fe2+ fuels Fenton reactions, generating ROS that drive lipid peroxidation and ferroptotic cell death. To maintain iron homeostasis, cells tightly regulate LIP levels through iron storage proteins such as ferritin and iron export mechanisms, including ferroportin. Notably, ferritinophagy—the selective autophagic degradation of ferritin—leads to iron release, thereby exacerbating iron overload and increasing ferroptosis sensitivity.[27–29] Furthermore, both ALOXs and POR require iron to catalyze their reactions,[30,31] highlighting that iron metabolism is implicated in all aspects of ferroptosis.
Ferroptosis can be effectively induced through precise regulation of both LIP levels and subcellular iron distribution. At the cellular level, activation of the p53/ferredoxin reductase/TFRC axis enhances iron uptake while inhibition of nuclear factor erythroid 2-related factor 2 (NRF2) downregulates iron storage proteins, such as ferritin light chain (FTL)/ferritin heavy chain (FTH1), and heme oxygenase 1 (HMOX1), both directly expanding the LIP.[32–35] Concurrently, targeting the APC membrane recruitment protein 1 (AMER1)/FTL complex promotes ubiquitination-mediated degradation of FTL,[36] releasing stored iron, whereas inhibiting the protein kinase B (Akt)/transient receptor potential mucolipin 1 (TRPML1) axis blocks lysosomal Fe2+ efflux, forcing lysosomal iron release into the cytosol to synergistically elevate the LIP.[37] At the subcellular level, suppressing the alpha-enolase 1 (ENO1)/iron regulatory protein 1 (IRP1)/mitoferrin 1 (MFRN1) pathway disrupts mitochondrial iron import,[38] while activating the signal transducer and activator of transcription 3 (STAT3)-dependent lysosomal death pathways exacerbates LIP accumulation through iron redistribution.[39] These strategies precisely regulate the iron metabolic network, enhancing lipid peroxidation and iron-dependent oxidative damage.

Antioxidant defense systems: Guardians against peroxidation
The GSH/GPX4 axis constitutes a central defense mechanism against ferroptosis by utilizing GSH as a reducing agent to catalyze the conversion of lipid hydroperoxides into non-toxic lipid alcohols via GPX4, thereby preventing oxidative damage to cellular membranes.[40,41] This process critically depends on the sufficient supply of cysteine, which is primarily imported in the form of cystine through system Xc−, a cystine/glutamate antiporter whose key functional subunit is solute carrier family 7 member 11 (SLC7A11). The activity of SLC7A11 is essential for maintaining intracellular GSH levels. Moreover, methionine metabolism reinforces this defense through the transsulfuration pathway to supply cysteine and generates S-adenosylmethionine (SAM) to epigenetically regulate GPX4 expression, thereby linking metabolism to ferroptosis resistance.[42–44] GPX4 then employs GSH to reduce lipid hydroperoxides to non-toxic lipid alcohols to prevent membrane damage. Erastin, a well-known ferroptosis inducer (FIN), triggers ferroptosis by inhibiting system Xc−, reducing cystine uptake. In contrast, Ras-selective lethal 3 (RSL3) induces ferroptosis by covalently binding to the selenocysteine active site of GPX4, inhibiting its phospholipid peroxidase activity.[5] However, cancer cells frequently use additional parallel antioxidant systems to counter ferroptosis. One such system involves the ferroptosis suppressor protein 1 (FSP1)/ubiquinone (CoQ10) pathway, where FSP1 reduces CoQ10 to ubiquinol (CoQ10H2), which acts as a radical-trapping antioxidant.[45–47] The dihydroorotate dehydrogenase (DHODH)/GTP cyclohydrolase-1 (GCH1) axis, comprising DHODH and GCH1, helps sustain mitochondrial CoQ10H2 and tetrahydrobiopterin levels by scavenging lipid radicals, further protecting cells from ferroptosis.[48,49]
Monounsaturated fatty acids (MUFA) are less prone to peroxidation and can replace PUFA in phospholipids, making cell membranes enriched with MUFA-PL more resistant to ferroptosis.[50,51] Stearoyl-CoA desaturase 1 (SCD1) mediates MUFA synthesis while acyl-CoA synthetase long-chain family member 3 (ACSL3) and membrane-bound O-acyltransferase domain-containing 1/2 (MBOAT 1/2) facilitate the incorporation of MUFA into PL, inhibiting ferroptosis.[50,52] In summary, tumors can evade ferroptosis through several mechanisms, leading to tumor progression. In clinical translation, enhancing ferroptosis mechanisms and targeting ferroptosis-evasion strategies could be employed to achieve antitumor effects.
The SLC7A11/GSH/GPX4 axis represents a central antioxidant pathway governing ferroptosis, with its functional disruption achievable through transcriptional and post-translational modifications of key components. At the transcriptional level, SLC7A11 expression is suppressed by activation of tumor suppressors, including p53 or BRCA1-associated protein 1 (BAP1), which lowers cystine uptake and limits GSH biosynthesis.[53–55] In contrast, oncogenic signals, such as the RAS pathway, enhance SLC7A11 transcription via E26 transformation-specific sequence 1 (ETS-1) and activating transcription factor 4 (ATF4) to sustain tumor survival.[56,57] Concurrently, inhibition of NRF2 blocks its transcriptional activation of SLC7A11, GPX4, and GSH-synthesizing enzymes, including the glutamate–cysteine ligase catalytic subunit (GCLC) and GSH synthetase, further weakening cellular antioxidant capacity.[58–61] Posttranslationally, the stability of SLC7A11 and GPX4 is dynamically regulated by ubiquitination. Activation of ubiquitin ligases, such as AMER1 or suppressors of cytokine signaling 2 (SOCS2), promotes SLC7A11 degradation,[36,62] whereas inhibition of deubiquitinases, including OTU deubiquitinase ubiquitin aldehyde binding 1 (OTUB1) or ubiquitin-specific peptidase 8 (USP8), encourages the degradation of these proteins.[63,64] Recent studies have shown that zinc finger DHHC-domain containing proteins 8 (ZDHHC8)[65] and 20 (ZDHHC20),[66] S-acyltransferases highly expressed in various cancers, are capable of palmitylating GPX4, thereby enhancing the stability of the protein. Furthermore, AMP-activated protein kinase (AMPK) inhibits the activity of SLC7A11 by phosphorylating beclin 1 (BECN1),[67] while suppression of the mechanistic target of rapamycin complex 2 (mTORC2) directly blocks SLC7A11-mediated cystine transport.[68] Pharmacologically, small-molecule agents, such as erastin and RSL3, disrupt axis functionality, while dual targeting of SLC7A11 and GPX4 synergistically amplifies ferroptosis by overwhelming the redox homeostasis.
Beyond the core pathway of ferroptosis, lipid metabolism and epigenetic modulation provide a multitude of therapeutic strategies. Inhibition of FSP1 impairs CoQ10 regeneration, weakening lipid radical scavenging.[69] Similarly, targeting vitamin K epoxide reductase complex subunit 1-like 1 (VKORC1L1) disrupts vitamin K-mediated antioxidant recycling.[70] Moreover, publicly available data from The Cancer Genome Atlas reveal that lower MLL4 expression is significantly associated with increased GPX4 expression in human head and neck squamous cell carcinoma (HNSCC) and bladder cancer. Consistently, in MLL4 conditional knockout mice, ferroptosis-suppressing genes such as GPX4, SLC7A11, and SCD1 are aberrantly upregulated.[19] However, YTH domain-containing protein 1 (YTHDC1)-dependent m6A modification accelerates FSP1 mRNA degradation.[71] Recent evidence indicates that lipoprotein uptake—a key determinant of ferroptosis sensitivity in cancer cells—occurs through sulfated glycosaminoglycan (GAG)-dependent pathways; targeting GAGs diminishes lipoprotein uptake and enhances ferroptosis sensitivity.[72] By integrating the targeting of auxiliary pathways with the core axis, a multidimensional attack network can be established to effectively block the tumor’s compensatory antioxidant escape mechanisms.

Crosstalk with pyroptosis and apoptosis
Ferroptosis does not exist in isolation within the cell death regulatory network. Instead, it is intricately interconnected with classical apoptosis and inflammatory pyroptosis through a complex and finely tuned crosstalk. This interplay is not only reflected in their potential activation by common stress signals, such as oxidative stress and mitochondrial dysfunction, but also in the presence of shared regulatory molecules that serve as pivotal nodes that bridge these distinct death pathways. These shared regulators influence the pathological progression of tumors, thereby informing the development of therapeutic strategies aimed at cell death.
The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, a central multiprotein complex composed of NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), and caspase-1, is responsible for sensing cellular danger signals and initiating pyroptosis. However, its function extends beyond pyroptosis, and it plays a crucial role in mediating the crosstalk between ferroptosis and apoptosis or pyroptosis.[73] Recent studies have shown that various apoptotic effectors directly contribute to the activation of the NLRP3 inflammasome and the secretion of interleukin (IL)-1β. For example, pro-apoptotic factors BCL2 antagonist/killer 1 (Bak) and BCL2-associated X (Bax) trigger the activation of the NLRP3 inflammasome by inducing the oxidation of mitochondrial DNA and promoting its release into the cytosol.[74] The anti-apoptotic protein cellular FADD-like IL-1β converting enzyme-like inhibitory protein (c-FLIP) facilitates inflammasome assembly by binding to NLRP3 and pro-caspase-1,[75] whereas the apoptotic adaptor fas-associated protein with death domain (FADD) regulates NLRP3 expression during the priming phase.[76] Caspase-8 and related proteases exert dual roles in modulating NLRP3 activation. In parallel, key regulators of ferroptosis are involved in the pyroptotic process.[77,78] GPX4, a major ferroptosis-suppressing enzyme, together with its essential reducing cofactor GSH, strongly inhibits activation of the NLRP3 inflammasome.[79,80] Conversely, ferroptosis and its promoting factors can drive NLRP3 activation. Lipid peroxidation products, such as oxidized phospholipids, and regulatory molecules, such as NRF2, whose deficiency impairs NLRP3 activation, can trigger IL-1β secretion and amplify pyroptosis.[81] NLRP3 can also modulate ferroptosis sensitivity through downstream signaling pathways, including Janus kinase 2 (JAK2) and STAT3, forming a complex and bidirectional regulatory loop.[82]
B-cell lymphoma 2 (BCL-2) family proteins, as central regulators of apoptosis, also play pivotal roles in the modulation of ferroptosis and pyroptosis. The anti-apoptotic protein BCL-2 not only suppresses apoptosis but also inhibits NLRP3 inflammasome activation induced by classical agonists or viral infection by regulating mitochondrial homeostasis and the activity of voltage-dependent anion channels voltage-dependent anion channel 2 (VDAC2) and voltage-dependent anion channel 3 (VDAC3), thereby negatively controlling the pyroptotic response.[83,84] More importantly, BCL-2 family members are directly involved in regulating ferroptosis. Anti-apoptotic proteins, such as BCL-2 and B-cell lymphoma-extra-large (BCL-xL), can physically bind to and inhibit VDAC2 and VDAC3, restricting mitochondrial function and ROS production, suppressing ferroptosis.[85] This function is independent of their anti-apoptotic activity. Conversely, inhibition of BCL-2, either through pharmacological agents or under certain pathological conditions, can promote Bax expression and modulate VDAC activity, ultimately inducing ferroptosis. Similarly, activation of pro-apoptotic proteins Bax and Bak not only triggers mitochondrial apoptosis but also facilitates mitochondrial lipid peroxidation and ferroptotic cell death.[86] This regulatory interplay has clear therapeutic implications. For example, the BCL-2 inhibitor navitoclax, in combination with targeted agents, such as the BTK inhibitor zanubrutinib, can synergistically induce ferroptosis in lymphoma cells by downregulating NRF2 and HMOX1 and suppressing GPX4 activity.[87]
In summary, targeting key shared regulatory nodes, such as the NLRP3 inflammasome and BCL-2 family proteins, offers an effective strategy to overcome therapeutic resistance caused by the inhibition of a single cell death pathway, while also achieving synergistic therapeutic effects. Elucidating the intricate crosstalk among ferroptosis, apoptosis, and pyroptosis—particularly the roles of NLRP3 and BCL-2 family members—will expand our understanding of cell death mechanisms. It also provides a solid theoretical foundation for the development of precision therapeutic strategies based on multipathway co-targeting, highlighting promising prospects for translational medicine.

Ferroptosis and Conventional Antitumor Therapy
Emerging evidence suggests that ferroptosis, as a novel therapeutic strategy, has been validated as effective in multiple cancer types, including non-small cell lung cancer (NSCLC), breast cancer (BC), gastric cancer (GC), colorectal cancer (CRC), pancreatic cancer (PC), and hepatocellular carcinoma (HCC). Recent studies have highlighted the critical role of ferroptosis in cancer therapy and its potential to overcome treatment resistance [Figure 3]. Notably, conventional therapies, including chemotherapy, radiotherapy, targeted therapy, and immunotherapy, can induce lipid peroxidation and trigger ferroptosis in tumor cells. Furthermore, ferroptosis induction has shown potential in resensitizing therapy-resistant malignancies by overcoming drug tolerance mechanisms [Table 1]. This dual capacity to directly eliminate tumor cells while reversing resistance underscores ferroptosis modulation as a promising therapeutic strategy.

Ferroptosis inducers
Given the critical role of ferroptosis in tumor suppression, various FINs have been identified or developed, including several existing small molecules or clinically approved drugs used for other diseases. As described in the mechanisms earlier, class I FINs refer to system Xc− inhibitors that suppress cystine import, including erastin and its analog imidazole ketone erastin (IKE), sorafenib, sulfasalazine (SSZ), and metformin. SSZ is a widely used anti-inflammatory drug for autoimmune diseases and has been shown to induce ferroptosis in a range of cancer cell lines. Metformin inhibits UFMylation of SLC7A11 and thus downregulates SLC7A11 expression to induce ferroptosis. Class II FINs inhibit or degrade GPX4, including RSL3, ML162, N6F11, Fin56, and cisplatin. Class III FINs deplete CoQ10, including inhibitor of ferroptosis suppressor protein 1 (iFSP1) and statins. Statins, commonly used to lower blood cholesterol, induce ferroptosis through inhibition of the FSP1-CoQ10 pathway. Moreover, class IV FINs promote lipid peroxidation through iron or PUFA overload, including lapatinib, artemisinin, and its derivatives (dihydroartemisinin and artesunate [Art]).[88] Beyond traditional drugs previously mentioned, preclinical evidence has identified specific natural compounds as effective FINs in tumor cells, notably curcumin,[89] shikonin,[90] tomatidine,[91] baicalin,[92] and isoliquiritigenin.[93] In addition, novel nano FINs have been developed based on these mechanisms and compounds. Using these inducers in drug development and therapy can effectively harness ferroptosis to eliminate tumor cells.

Ferroptosis and chemotherapy
The traditional antitumor mechanism of cisplatin primarily involves inducing a DNA damage response that leads to apoptosis.[94,95] Recent studies have found that cisplatin also functions as a Class II FIN, depleting GSH and inhibiting GPX4 activity, thereby synergistically triggering lipid peroxidation-mediated ferroptosis.[95,96] However, tumor cells can evade cisplatin-induced cytotoxicity and develop resistance by activating ferroptosis-inhibitory pathways, such as by upregulating SLC7A11 or GPX4. For instance, in NSCLC, high expression of spectrin beta non-erythrocytic 2 enhances cisplatin resistance by promoting the membrane localization of SLC7A11, thereby suppressing ferroptosis.[97] Conversely, MAF BZIP transcription factor F (MAFF) induces ferroptosis by transcriptionally downregulating SLC7A11. A decrease in MAFF expression weakens this regulatory mechanism, serving as a terminal regulatory event in cisplatin resistance in lung adenocarcinoma (LUAD).[98] In GC, dysregulated Wnt/β-catenin signaling drives tumor progression and chemoresistance through ferroptosis modulation. Mechanistically, the β-catenin/transcription factor 4 (TCF4) complex transcriptionally upregulates GPX4 by binding its promoter, which suppresses lipid ROS generation and reinforces antioxidant defenses. Genetic ablation of TCF4 potentiates cisplatin-triggered ferroptosis.[94] Cisplatin-resistant cells activate the NRF2/kelch-like ECH-associated protein 1 (KEAP1)/SLC7A11 axis to evade ferroptosis, while ATF3-mediated suppression of this pathway resensitizes cells to ferroptosis and overcomes drug resistance.[99] These parallel mechanisms highlight the therapeutic potential of dual targeting of the Wnt/β-catenin/TCF4 cascade and the NRF2-mediated antioxidant system to combat cisplatin resistance in GC. In cisplatin-resistant HNSCC, inducing glutaredoxin 5 dysfunction disrupts mitochondrial iron–sulfur cluster biosynthesis, thereby impairing iron regulatory protein and ferrochelatase activity. This dysregulation leads to LIP imbalance, free iron overload, and mitochondrial iron accumulation, ultimately triggering lipid ROS-driven ferroptosis to counteract chemoresistance.[100]
Triple-negative BC exhibits distinct ferroptosis regulation through tumor-associated macrophage-derived transforming growth factor (TGF)-β1, which activates hepatic leukemia factor (HLF) to transcriptionally upregulate gamma-glutamyltransferase 1 (GGT1). The ensuing GSH metabolic rewiring reinforces the GPX4-mediated antioxidant defense, establishing ferroptosis resistance while simultaneously driving malignant progression and cisplatin tolerance.[101] Notably, preclinical studies across diverse cancer models indicate that cisplatin combination therapy with FINs shows promise in overcoming chemoresistance. In ovarian cancer (OC) models, shikonin synergizes with cisplatin by upregulating HMOX1 to promote Fe2+ accumulation, significantly enhancing ferroptosis and reversing cisplatin resistance,[90] while short-term erastin pretreatment restores redox homeostasis and resensitizes resistant cells to cisplatin. Further studies in head and neck cancer have demonstrated the advantages of combination therapy, for example, although Art is a ferroptosis inducer, it can activate the Nrf2–antioxidant response element (ARE) pathway to counteract ferroptosis, whereas Nrf2 inhibition synergistically enhances the cytotoxic effects of artesunate and cisplatin.[102] Moreover, SSZ reverses cisplatin resistance in preclinical models by specifically inducing ferroptosis.[103] These findings collectively demonstrate that combining cisplatin with other FINs is a promising antitumor strategy. What is more, ceramide kinase inhibitor NVP-231 can enhance the therapeutic sensitivity of cisplatin by inducing ferroptosis and oxidative stress.[104] In summary, cisplatin-induced ferroptosis not only complements its canonical DNA damage mechanism but, more critically, drives tumor cells to activate ferroptosis resistance pathways that promote chemoresistance. Targeting these resistance pathways represents an emerging therapeutic strategy to overcome treatment resistance. Although the molecular regulators of ferroptosis evasion vary across different cancer types, the central mechanism commonly involves the upregulation of SLC7A11/GPX4 or the enhancement of GSH metabolism, thereby establishing antioxidant defenses to counteract lipid peroxidation. This shared feature provides a theoretical foundation for developing broad-spectrum or cancer-type-specific strategies to sensitize tumors to ferroptosis.
Gemcitabine (GEM) exerts its antitumor effects by inducing S-phase arrest through the disruption of DNA synthesis. The accumulation of ROS observed during GEM treatment may contribute to the activation of the ferroptosis pathway.[105,106] Mechanistically, in pancreatic ductal adenocarcinoma (PDAC), GEM upregulates the expression of the p22phox subunit by activating the NF-κB signaling pathway, thereby promoting NADPH oxidase (NOX)-dependent ROS generation.[105] Tumor cells facilitate chemoresistance by activating adaptive ferroptosis resistance mechanisms, some of which are linked to GPX4 regulation in PC, a malignancy with a dismal prognosis, demonstrating significant gemcitabine resistance. For example, high-mobility group AT-hook 2 upregulates GPX4 expression to enhance cell survival under gemcitabine treatment,[107] while AT-rich interactive domain-containing protein 3A (ARID3A) reduces lipid peroxidation by transcriptionally elevating GPX4 levels via the regulation of phosphatase and tensin homolog (PTEN) induction.[108] Small mothers against decapentaplegic 4 (SMAD4) directly suppresses GPX4 transcription by binding to its promoter, and its combination with RSL3 synergistically induces ferroptosis to augment chemosensitivity.[109] Meanwhile, the ATF4/heat shock protein (HSP) family A member 5 (HSPA5) axis inhibits lipid peroxidation by stabilizing the GPX4 protein.[110] In lipid metabolism regulation, nuclear receptor coactivator 6 (NCOA6) induces SCD1 expression while downregulating ACSL4, and its knockdown reverses gemcitabine resistance.[111,112] Further studies have demonstrated that carnitine palmitoyltransferase 1B (CPT1B) maintains lipid peroxidation suppression through the KEAP1/NRF2 axis,[113] whereas F-box and WD repeat domain-containing 7 (FBXW7) reduces lipid peroxidation by inhibiting SCD1 to drive resistance.[114] In addition, tripartite motif-containing 21 (TRIM21) promotes tumor progression and resistance by disrupting epoxide hydrolase 1 (EPHX1)-mediated AA metabolism.[115] In parallel, NRF2 overexpression autonomously sustains redox homeostasis by enhancing GSH synthesis beyond the regulation of GPX4.[116] These interconnected networks underscore the pivotal role of ferroptosis evasion in gemcitabine chemoresistance. Combination therapies enhance chemosensitivity through the induction of ferroptosis through several pathways. For example, gemcitabine combined with cisplatin synergistically triggers ferroptosis in PDAC by suppressing the transcription factor specificity protein 1 (SP1), which leads to the upregulation of SAT1. This process accelerates the catabolism of spermidine and spermine, resulting in increased iron accumulation and lipid peroxidation.[117] In LUAD, gemcitabine combined with erastin enhances ferroptosis-mediated cytotoxicity through the knockdown of kinesin family member 20A (KIF20A).[118] Notably, gemcitabine–RSL3 co-treatment exerts dual therapeutic effects by directly inducing ferroptosis and antagonizing the GSH/GPX4 antioxidant axis to restore chemosensitivity in resistant cells.[109,114] Tomatidine, a natural compound, inhibits ATF4 nuclear translocation, thereby obstructing its transcriptional activation of GPX4 and increasing lipid peroxidation to sensitize PDAC cells to gemcitabine.[91] These findings indicate that targeting ferroptosis regulatory networks provides a multi-pronged strategy to overcome chemoresistance barriers.
Some chemotherapeutic drugs may not directly trigger ferroptosis; however, their resistance mechanisms are frequently associated with pathways that facilitate the escape from ferroptosis. Therefore, targeting ferroptosis can synergistically reverse their resistant states. Research on 5-fluorouracil (5-FU) resistance mechanisms indicates that both GC and CRC demonstrate changes in the regulatory networks associated with ferroptosis. STAT3 blocks lipid peroxidation by upregulating ferroptosis suppressors (GPX4, SLC7A11, and FTH1). Conversely, the inhibition of STAT3 reactivates ferroptosis, thereby restoring 5-FU sensitivity in GC.[119] The aberrant subcellular localization of mitochondrial DHODH enhances ferroptosis resistance in resistant CRC cells, while DHODH depletion reinstates chemosensitivity by activating lipid peroxidation.[120] Research on lipid metabolism has revealed that excessive lipid droplet accumulation in CRC forms a resistance barrier via diacylglycerol acyltransferase (DGAT)-dependent homeostasis, and DGAT inhibition disrupts lipid equilibrium to induce ferroptosis.[121] Lipocalin 2 (LCN2) inhibits ferroptosis by reducing intracellular iron concentrations and upregulating GPX4/SLC7A11, whereas the silencing of LCN2 amplifies the effectiveness of 5-FU both in vitro and in vivo.[122] In mitochondrial regulation, WW domain-binding protein 1 (WBP1) suppresses ferroptosis by maintaining mitochondrial respiration, and its absence renders resistant CRC cells more susceptible to 5-FU/oxaliplatin.[123] Similarly, in GC, syntaxin 1A (STX1A) sustains mitochondrial function to alleviate oxidative stress, and targeting STX1A induces ferroptosis to reverse 5-FU/cisplatin resistance.[124] HtrA serine protease 1 (HTRA1) drives 5-FU resistance via SLC7A11 overexpression,[125] while pyrroline-5-carboxylate reductase 1 (PYCR1) inhibits lipid ROS production by promoting SLC25A10 expression, and genetic silencing of PYCR1 amplifies the anticancer efficacy of 5-FU.[126] Collectively, these mechanisms contribute to the evasion of ferroptosis in chemoresistance associated with gastrointestinal cancer. Combination therapies enhance 5-FU cytotoxicity by amplifying ferroptosis. For example, the Jianpi Jiedu decoction reverses CRC 5-FU resistance by inhibiting the SLC7A11/GSH/GPX4 axis,[127] while Schisandrin A overcomes GC resistance through transferrin receptor upregulation-mediated iron accumulation and lipid peroxidation.[128] Baicalin improves the 5-FU response in GC through ROS-dependent ferroptosis,[92] whereas metformin restores CRC chemosensitivity by targeting the family with sequence similarity 98 member A (FAM98A)-regulated SLC7A11 expression in stress granules.[129] Flubendazole, which induces p53, synergizes with 5-FU in castration-resistant PC, leading to cell cycle arrest and ferroptosis co-activation.[130] Furthermore, andrographolide combined with 5-FU amplifies the treatment effectiveness against CRC by modulating ferroptosis and Wnt pathway components, including HMOX1, GCLC, glutamate-cysteine ligase modifier subunit, and T-cell factor 7-like 2.[131] Together, these findings support the role of multidimensional mechanisms in ferroptosis-modulating combination tactics to surmount drug resistance in gastrointestinal cancer.
Oxaliplatin, a third-generation platinum-based chemotherapeutic drug, exerts its antitumor effects primarily through DNA interstrand crosslink-induced replication blockage and is extensively used in many cancer types. Recent evidence indicates that ferroptosis evasion represents a key contributor in the development of acquired resistance to oxaliplatin. In resistant CRC cells, KIF20A promotes GPX4 transcription through the NUAK family kinase 1 (NUAK1)/NRF2 signaling axis, thereby inhibiting lipid peroxidation,[132] while cyclin-dependent kinase 1 (CDK1) suppresses ferroptosis by promoting the ubiquitination and degradation of ACSL4, thereby diminishing oxaliplatin-induced chemotherapeutic damage.[133] As a rate-limiting enzyme for iron–sulfur cluster biosynthesis, cysteine desulfurase (NFS1) antagonizes ferroptosis by reducing ROS generation, and its specific inhibition significantly enhances oxaliplatin cytotoxicity.[134] Notably, chromobox 3 (CBX3) overexpression inhibits the transcriptional activity of CUL3, which encodes cullin-3, through direct promoter binding, impairing NRF2 degradation and upregulating downstream glutathione peroxidase 2 (GPX2) expression, thereby facilitating multidrug resistance to irinotecan and oxaliplatin.[135] Conversely, ubiquitin protein ligase E3 component N-recognin 5 (UBR5) stabilizes SMAD3 via lysine 11 (K11)-linked polyubiquitination, suppressing ATF3 transcription and upregulating SLC7A11 expression to establish a ferroptosis-resistant network.[136] Furthermore, RNA-binding motif single-stranded interacting protein 1 (RBMS1) enhances ferroptosis tolerance by promoting prion protein (PRNP) translation, and its silencing restores oxaliplatin sensitivity in CRC cells,[137] whereas the lncRNA small nucleolar RNA host gene 4 (SNHG4) inhibits ferroptosis by destabilizing the PTEN protein, promoting drug-resistant phenotypes.[138] Oxaliplatin-activated mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling phosphorylates radical fringe (RFNG) to facilitate importin-α1/β1 complex formation, which suppresses p53 phosphorylation, downregulates cyclin-dependent kinase inhibitor 1A (CDKN1A), and upregulates SLC7A11 to inhibit both apoptosis and ferroptosis. In contrast, phosphorylation-deficient RFNG enhances cell death signals and reverses chemoresistance.[139] Within metabolic microenvironments, elevated microsomal triglyceride transfer protein (MTTP)/proline-rich acidic protein 1 (PRAP1) complexes in plasma exosomes of obese CRC patients inhibit zinc finger E-box binding homeobox 1 (ZEB1) while upregulating GPX4 and SLC7A11, and MTTP targeting restores oxaliplatin sensitivity.[140] In PC, Krüppel-like factor 5 (KLF5) downregulates HMOX1 expression by suppressing ZEB1, and KLF5 inhibition in combination with oxaliplatin significantly inhibits tumor growth.[141] In HCC, oxaliplatin chemotherapy activates epidermal growth factor receptor (EGFR) signaling to drive lysyl oxidase like 3 (LOXL3)–translocase of outer mitochondrial membrane 20 (TOM20) interaction and adenylate kinase 2 (AK2)-mediated phosphorylation, ultimately blocking mitochondrial ferroptosis by inhibiting DHODH degradation.[142] Simultaneously, ubiquitin-specific peptidase 20 (USP20) stabilizes SLC7A11 through a ubiquitin c-terminal hydrolase domain-mediated interaction, reducing its ubiquitination and inducing chemoresistance in HCC.[143] Combination strategies demonstrate broad-spectrum sensitization effects, where oxaliplatin plus polyenylphosphatidylcholine (PPC) enhances ROS accumulation and ferroptosis signals in GC via NRF2 nuclear translocation-mediated HMOX1 upregulation,[144] while butyrate synergistically potentiates oxaliplatin-induced ferroptosis by inhibiting system Xc−-dependent GSH synthesis.[145] Together, these findings elucidate tumor type-specific ferroptosis evasion mechanisms contributing to oxaliplatin resistance and provide a robust experimental rationale for cross-cancer combination therapies aimed at overcoming therapeutic resistance.

Ferroptosis and targeted therapy
Sorafenib, as the first systemic drug approved by the FDA for first-line treatment of HCC, functions not only as a multi-kinase inhibitor but also induces ferroptosis by suppressing SLC7A11 and GPX4 expression while promoting malondialdehyde generation.[146,147] Beyond HCC, recent studies have revealed its broader regulatory role in ferroptosis. For example, in NSCLC, sorafenib inhibits endogenous STAT3 activation and downregulates myeloid cell leukemia 1 (MCL1) protein expression, leading to the release of the ferroptosis driver BECN1 from the BECN1/MCL1 complex, which subsequently suppresses SLC7A11 activity and enhances ferroptosis.[148] However, tumor cells develop resistance to sorafenib through multiple ferroptosis-evasion mechanisms involving noncoding RNAs, signaling pathways, and metabolic reprogramming. At the noncoding RNA level, circular RNA circTTC13 promotes drug resistance by inhibiting ferroptosis through sponging miR-513a-5p, thereby relieving its suppressive effect on SLC7A11 expression,[149] while lncRNA metastasis-associated LUAD transcript 1 (MALAT1) stabilizes SLC7A11 mRNA through ELAV-like RNA-binding protein 1 (ELAVL1) binding, thereby antagonizing sorafenib-induced ferroptosis.[150] Hepatocyte nuclear factor 4 alpha antisense RNA 1 (HNF4A-AS1), a lipid metabolism-associated lncRNA, interacts with methyltransferase-like 3 (METTL3) to downregulate 2,4-dienoyl-CoA reductase 1 (DECR1) expression, thereby reducing PUFA synthesis and lowering ferroptosis sensitivity.[151] Furthermore, the lncRNA plasmacytoma variant translocation 1 (PVT1) promotes sorafenib resistance by transcriptionally upregulating GPX4.[152] Regarding signaling pathways, aspartate β-hydroxylase (ASPH) suppresses ferroptosis through activating the sequestosome 1 (SQSTM1)/p62 autophagy pathway and the SLC7A11/GPX4 axis, and sorafenib-induced autophagy enhancement is attenuated upon ASPH knockout, restoring drug sensitivity.[153] In addition, stromal interaction molecule 1 (STIM1) activates SLC7A11 transcription through the store-operated calcium entry (SOCE)/calcineurin (CaN)/nuclear factor of activated T-cells (NFAT) signaling axis, thereby promoting resistance.[154] Meanwhile, deficiency of dead-box helicase 5 (DDX5) activates the Wnt/β-catenin/NRF2 pathway, enabling HCC cells to evade ferroptosis during sorafenib treatment.[155] Furthermore, loss of leukemia inhibitory factor receptor (LIFR) upregulates LCN2 through the src-homology 2 domain-containing protein tyrosine phosphatase 1 (SHP1)/NF-κB pathway, sequestering intracellular iron and antagonizing ferroptosis.[156] In clear cell renal cell carcinoma (RCC), dipeptidyl peptidase 9 (DPP9) competitively binds KEAP1, displacing NRF2 and enhancing its transcriptional activity, which promotes SLC7A11 expression, suppresses ROS generation, and induces sorafenib resistance.[157] From a metabolic perspective, glutathione S-transferase alpha 1 (GSTA1) limits ferroptosis through its peroxidase activity that clears lipid peroxides.[158] Meanwhile, deficiency of solute carrier family 27 member 5 (SLC27A5) leads to NRF2-dependent upregulation of glutathione reductase (GSR), maintaining GSH homeostasis, and combined treatment with sorafenib and the GSR inhibitor carmustine enhances ferroptosis.[159] In mitochondria, general control of amino acid synthesis 5-like 1 (GCN5L1) maintains iron homeostasis in HCC by modulating CDGSH iron–sulfur domain 1 (CISD1),[160] while in cervical cancer, mitochondrial carrier 1 (MTCH1) deficiency disrupts oxidative phosphorylation and elevates mitochondrial ROS levels, enhancing sorafenib efficacy.[161] Regarding iron metabolism pathways, dual-specificity phosphatase 4 (DUSP4) reduces ferroptosis by phosphorylating YTHDC1 to alter FTL/FTH1 mRNA localization.[162] Chaperonin-containing TCP1 subunit 3 (CCT3) inhibits TFRC recycling through K21 ubiquitination and interaction with alpha-actinin 4 (ACTN4), thereby impeding iron uptake.[163] These findings not only mechanistically describe the complex ferroptosis-suppressive network underlying sorafenib resistance but also highlight key molecular targets for potential combination therapies. Some studies have already developed preliminary treatment strategies to overcome resistance by using drug combination approaches. For example, dihydroartemisinin enhances sorafenib sensitivity in HCC by suppressing ATF4-mediated SLC7A11 activity, thereby promoting lipid peroxidation and ferroptosis.[164] Similarly, metformin downregulates ATF4 to inhibit STAT3 phosphorylation and nuclear translocation, elevating ROS and lipid peroxidation levels to overcome resistance.[165] The combination of sorafenib with camptothecin, an NRF2 inhibitor, synergistically increases lipid peroxidation and iron levels, suppresses GPX4 activity, downregulates NRF2 and SLC7A11, and enhances intracellular sorafenib accumulation.[166] In p53 wild-type HCC models, the short-chain acyl-CoA dehydrogenase 1 (SCAD1) inhibitor aramchol combined with donafenib (a deuterated sorafenib derivative) exhibits potent antitumor effects by counteracting p53 ubiquitination and SCAD1 upregulation.[167] In addition, boric acid amplifies sorafenib cytotoxicity in HCC by elevating intracellular ROS levels.[168] Ursolic acid, a natural pentacyclic triterpenoid, synergizes with sorafenib to suppress SLC7A11, intensifying lipid ROS accumulation.[169] Moreover, phosphoseryl-tRNA kinase (PSTK) deficiency inactivates GPX4 and disrupts GSH metabolism, and punicalin (a putative PSTK inhibitor) combined with sorafenib shows synergistic efficacy in preclinical HCC models.[170] Importantly, sorafenib-induced mitochondrial dysfunction triggers macrophagy-mediated cysteine replenishment to counteract ferroptosis, while amiloride inhibits this process to resensitize resistant HCC to sorafenib.[171] These findings suggest that combination therapies can partially overcome resistance to sorafenib during treatment. Beyond its kinase-targeting activity, sorafenib’s ability to induce ferroptosis represents a critical breakthrough in overcoming drug resistance. Although current combination strategies can partially reverse resistance, they still face two major challenges: managing target-associated toxicity and addressing the spatiotemporal dynamics of resistance. Future research should focus on developing spatiotemporally precise intervention strategies to dismantle this “multidimensional defense fortress”.
EGFR-positive NSCLC may develop resistance to gefitinib, a first-generation EGFR-tyrosine kinase inhibitor (TKI), and dysregulation of ferroptosis is a critical mediator. For example, inhibition of aldo-keto reductase family 1 member C1 (AKR1C1) prevents the reduction of lipid peroxides (LPOs), thereby restoring the sensitivity of LUAD cells to gefitinib.[172] Origin recognition complex subunit 1 (ORC1) promotes the proliferation of LUAD cells by regulating the expression of SLC7A11 and inhibits gefitinib-induced ferroptosis.[173] In addition, fat mass and obesity-associated gene (FTO) suppresses the maturation of miR-138-5p, which can induce ferroptosis by targeting LCN2; silencing FTO enhances the sensitivity of LUAD to gefitinib treatment.[174] In NSCLC, ubiquitin-specific peptidase 22 (USP22) stabilizes mouse double minute 2 homolog (MDM2) to block ferroptosis,[175] while discoidin domain receptor 1 (DDR1) overexpression is associated with poor prognosis and resistance, which can be reversed by targeting DDR1 to upregulate SOCS2 and activate ferroptosis.[176] In gefitinib-resistant cells, silencing phosphoenolpyruvate carboxykinase 2 (PCK2) can induce ferroptosis by inhibiting GPX4 and SLC7A11, while increasing ACSL4 levels. Notably, in vivo, PCK2 knockdown synergizes with gefitinib to suppress tumor growth, confirming ferroptosis induction as a therapeutic amplifier.[177] Interestingly, apoptosis-associated tyrosine kinase (AATK) localizes to both early and recycling endosomes, and its high expression inhibits ferroptosis by delaying endosomal recycling, thus reducing intracellular Fe2+ levels. Conversely, AATK downregulation promotes endosomal recycling and iron accumulation, significantly increasing ferroptosis sensitivity in gefitinib-resistant lung cancer cells.[178] In terms of combination therapy, studies on drug resistance in gastrointestinal stromal tumors have shown that residual resistant cells exhibit enhanced sensitivity to the GPX4 inhibitor RSL3 due to decreased GSH levels resulting from downregulated glucose metabolism. RSL3 effectively suppresses the growth of residual lung cancer cells following gefitinib treatment.[179] The novel dual-targeting thioredoxin reductase (TrxR)–EGFR gold complex L1Au1 induces ferroptosis by promoting GPX4 degradation through both autophagolysosomal and proteasomal pathways, offering a new strategy for overcoming lung cancer resistance through the development of TrxR–EGFR-targeted gefitinib derivatives.[180] These findings suggest that gefitinib resistance is closely associated with the escape from ferroptosis through multiple pathways. Targeting these key nodes to reactivate lipid peroxidation and ferroptosis not only overcomes resistance but also proposes a combination strategy to enhance the efficacy of EGFR-TKIs, making ferroptosis regulation a key direction for the treatment of refractory tumors.
Lapatinib, a standard salvage therapy for advanced BC, exerts antitumor effects not only through conventional signaling inhibition but also by inducing ferroptosis in various cancer types. In CRC, lapatinib suppresses GPX4 expression, resulting in elevated ROS and malondialdehyde levels, which can be partially reversed by the ferroptosis inhibitor Ferrostatin-1.[181] Lapatinib also demonstrates potent growth inhibition as a FIN in KRASG12C inhibitor-resistant models.[182] However, in lapatinib-resistant NSCLC, activation of mammalian target of rapamycin complex 1 (mTORC1) upregulates GPX4, counteracting ferroptosis. Notably, silencing GPX4 restores ferroptosis sensitivity and enhances lapatinib efficacy in vivo, suggesting that dual targeting of GPX4/mTOR could be a viable strategy for overcoming resistance.[183] Combination approaches have shown synergistic potential. For instance, pairing lapatinib with the lysosome disruptor siramesine induces ferroptosis in BC through ROS elevation and Fe2+ accumulation.[184] Conversely, combining low-dose abietic acid with lapatinib downregulates PDZ domain-containing 8 expression, leading to mitochondrial iron accumulation and enhanced H2O2 generation for synergistic antitumor effects.[185] In PC, lapatinib counteracts solute carrier family 35, member F2 (SLC35F2)-mediated p53 degradation, potentiating tumor suppression by IKE, an inducer of ferroptosis, in vivo.[186] These multifaceted findings underscore lapatinib’s broad ferroptosis-inducing capacity and its combinatorial therapeutic potential against diverse resistant malignancies.
Olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor clinically approved for tumors harboring BRCA1/2 mutations, has shown expanded therapeutic mechanisms through the regulation of ferroptosis. Specifically, in OC, PARP activation upregulates SLC7A11 through p53-dependent pathways, suppressing ferroptosis. Olaparib partially counteracts this effect by inhibiting SLC7A11-mediated GSH synthesis. Notably, combining FINs with olaparib significantly enhances therapeutic sensitivity in BRCA-high tumor cells.[187] In olaparib-resistant OC cells, overexpression of sphingosine kinase 1 (SPHK1) activates the NF-κB pathway to inhibit ferroptosis. Importantly, the SPHK1 inhibitor PF-543 synergizes with olaparib to restore ferroptosis, highlighting the clinical potential of this combination strategy.[188] Furthermore, combining olaparib with apatinib induces ferroptosis in OC by suppressing NRF2 signaling and autophagy pathways to downregulate GPX4 expression.[189] Another study demonstrated that olaparib synergizes with arsenic trioxide to activate the AMPK/SCD1 signaling axis, effectively inducing ferroptosis and overcoming drug resistance.[190] The TrxR inhibitor auranofin (AF), at high concentrations, cooperates with olaparib to enhance ROS generation and cytotoxicity in AF-resistant NSCLC and PDAC cell lines with low levels of mutant p53 protein.[191] These findings illustrate the multidimensional ferroptosis-modulating mechanisms of olaparib and underscore the broad therapeutic potential of its combinatorial applications.
Cetuximab is a monoclonal antibody that primarily targets EGFR and is used to treat various cancers, particularly CRC and head and neck cancer. In KRAS-mutant CRC, cetuximab suppresses the NRF2/HMOX1 axis to promote ferroptosis and shows synergy with RSL3, β-elemene, and 3-bromopyruvate, further amplifying this effect.[192–194] Notably, 3-bromopyruvate overcomes cetuximab resistance by blocking SLC7A11 activity, thereby restoring ferroptosis in refractory CRC cells.[195] In HNSCC, loss of epiregulin downregulates GPX4, inducing ferroptosis and resensitizing tumors to cetuximab.[196] These findings reveal that cetuximab resistance arises from the adaptive activation of ferroptosis-suppressing pathways, such as NRF2, SLC7A11, and GPX4. Targeting these pathways in combination reactivates lipid peroxidation-driven cell death, highlighting ferroptosis induction as a promising strategy to enhance cetuximab efficacy in resistant malignancies.
Sunitinib, a multitarget TKI primarily targeting vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and c-KIT, is FDA-approved as a first-line therapy for advanced RCC and as a second-line treatment for imatinib-resistant gastrointestinal stromal tumors. RCC progression is closely associated with absent in melanoma 2 (AIM2)-mediated suppression of ferroptosis. Specifically, AIM2 triggers phosphorylation-dependent ubiquitin-proteasomal degradation of forkhead box O3a (FOXO3a), severely impairing its transcriptional activation of ACSL4 and enhancing RCC cell resistance to ferroptosis. Targeting the AIM2 signaling axis restores sunitinib sensitivity and reverses resistant phenotypes, underscoring the central role of the AIM2/FOXO3a/ACSL4 pathway in RCC microenvironment remodeling.[197] Curcumin has been shown to enhance the sensitivity of clear cell RCC to sunitinib by downregulating the expression of FTH1, suggesting its potential as a resistance-reversing agent.[198] Artesunate, a class III FIN, suppresses sunitinib-resistant RCC growth via dual mechanisms of cell cycle arrest and ferroptosis induction. Artesunate treatment elevates p53 expression, reduces GSH levels, and enhances ROS production in both parental and sunitinib-resistant RCC cells.[89] Importantly, in sunitinib-resistant RCC models, IL-6 emerges as an upstream regulator that activates SLC7A11 expression through the JAK2/STAT3 axis, leading to ferroptosis blockade and TKI resistance. This mechanism offers novel therapeutic avenues to address targeted therapy resistance in advanced RCC.[199] Collectively, these findings highlight ferroptosis modulation as a central strategy to overcome sunitinib resistance and optimize combination therapies.

Ferroptosis and radiotherapy
Ferroptosis is induced by triggering oxidative stress and lipid peroxidation, thereby suppressing tumor proliferation. Conversely, aberrant activation of ferroptosis-related regulatory networks, such as upregulation of the GPX4/SLC7A11 pathway, may mediate radioresistance and promote tumor cell survival.[200,201] This bidirectional regulatory mechanism underscores the therapeutic potential of targeting key ferroptosis molecules (GPX4 and SLC7A11) to enhance radiotherapy efficacy and overcome resistance, offering a mechanism-driven approach to improve treatment outcomes in radiation-refractory cancers.
Radiotherapy influences ferroptosis regulation through multiple mechanisms. First, radiotherapy suppresses SLC7A11 expression by activating the ataxia-telangiectasia mutated (ATM) gene, thereby enhancing lipid peroxidation and ferroptosis in tumor cells.[202] Second, ionizing radiation (IR)-induced double-stranded DNA (dsDNA) activates cGAS signaling, which further promotes ferroptosis via the ATF3/SLC7A11 axis.[203] Furthermore, glutathione S-transferase mu 3 (GSTM3) is upregulated after IR exposure, stabilizing ubiquitin-specific peptidase 14 (USP14), which reduces the ubiquitination and degradation of fatty acid synthase (FASN) and inhibits the expression of GPX4, thereby dual-inducing ferroptosis.[204] Simultaneously, IR upregulates MAFF expression in LUAD cells, promoting radiosensitivity by inducing ferroptosis through the regulation of SLC7A11.[98] Radiotherapy affects not only the SLC7A11/GPX4 axis but also induces ferroptosis through other mechanisms. For instance, it increases ROS production and upregulates ACSL4 expression, promoting PUFA-PL formation, ultimately leading to ferroptotic cell death.[205] Moreover, radiated tumor cell-released microparticles (RT-MPs) can directly induce ferroptosis, thereby exerting antitumor effects. These microparticles may also cause oxidative stress and DNA damage in both irradiated cancer cells and adjacent non-irradiated cells or tissues, a phenomenon known as the radiation-induced bystander effect (RIBE).[206]
Concurrently, studies have demonstrated that IR may paradoxically contribute to radiotherapy resistance by inhibiting ferroptosis in tumor cells. For instance, stanniocalcin 2 (STC2) promotes radiotherapy resistance in esophageal squamous cell carcinoma (ESCC) by activating protein methyltransferase 5 (PRMT5) and suppressing ferroptosis through the SLC7A11-mediated pathway.[207] IR downregulates copper metabolism MURR1 domain-containing protein 10 (COMMD10), leading to reduced intracellular iron levels and activation of the hypoxia inducible factor 1 subunit alpha (HIF1α)/SLC7A11 axis, which in turn inhibits ferroptosis and contributes to radiotherapy resistance in HCC.[208] Conversely, simultaneous inhibition of SLC7A11 or GPX4 during radiotherapy has been shown to enhance radiosensitivity. For example, SOCS2, identified as a predictor of radiotherapy response, promotes SLC7A11 ubiquitination and degradation, thereby inducing ferroptosis and sensitizing HCC cells to radiation therapy.[62] Notably, in glioblastoma multiforme (GBM), interferon-inducible protein 16 (IFI16) attenuates ferroptosis post-radiation by activating HMOX1 transcription, thereby reducing lipid peroxidation, ROS generation, and Fe2+ accumulation. Conversely, glyburide restores ferroptosis and significantly improves radiosensitivity by disrupting IFI16 function.[209]
Recent studies have increasingly focused on enhancing tumor radiosensitivity through ferroptosis induction, demonstrating significant potential across multiple cancer types. In NSCLC, miR-139 suppresses the NRF2 signaling pathway, thereby exacerbating IR-induced lipid peroxidation and promoting ferroptosis.[210] Besides, radiotherapy-sensitive NSCLC tissues upregulate phosphorylase kinase catalytic subunit gamma 2 (PHKG2) expression to promote ferritinophagy, increasing intracellular iron levels and amplifying mitochondrial stress-dependent ferroptosis post-radiation.[211] In esophageal squamous cell carcinoma, the NRF2 inhibitor ML385 serves as an effective radiosensitizer by targeting SLC7A11 to induce ferroptosis.[212] Further investigations reveal that radiotherapy exerts dual effects: it disrupts iron homeostasis and triggers ferroptosis through the interferon regulatory factor 1(IRF1)/TFRC axis, increasing intracellular Fe2+ concentrations, while simultaneously inducing glutamine accumulation and upregulating the glutamine transporter SLC1A5 in HNSCC. Blocking glutamine metabolism synergistically enhances radiotherapy efficacy in HNSCC.[213] In advanced HCC, the Toll-like receptor 3 (TLR3) agonist poly(I:C) potentiates the abscopal effect of radiotherapy by activating ferroptosis signaling.[214] In addition, as a novel FIN, tubastatin A directly binds to and inhibits GPX4 enzymatic activity, significantly promoting radiation-associated lipid peroxidation and suppressing tumor growth in mouse xenograft models.[215] At the technological frontier, nanomaterials offer innovative approaches for ferroptosis-mediated radiosensitization. For instance, gold/copper nanocomposites (Au/CuNDs) induce ferroptosis through multipathway ROS generation to achieve radiosensitization,[216] while oxygen vacancy-rich, iron-free radiosensitizers such as oxygen vacancies (ovs)-manganese dioxide (MnO2) enhance radiotherapy efficacy by releasing intracellular free Fe2+, accumulating ROS, and intensifying lipid peroxidation.[217] Consequently, targeting ferroptosis in tumor cells emerges as a promising therapeutic strategy to enhance radiosensitization and overcome radioresistance.
Although the molecular mechanisms underlying radiotherapy-induced ferroptosis have been partially elucidated, important limitations remain. In particular, the specific molecular pathways governing radiotherapy-triggered ferroptosis are not yet fully characterized, especially given the considerable heterogeneity across cancer types and treatment contexts. Future research should prioritize clarifying the complex crosstalk between ferroptosis and radiotherapy, aiming to enhance therapeutic efficacy through precision modulation of ferroptosis pathways using nanotechnology or small-molecule agents. Furthermore, considering that ferroptosis resistance may constitute a fundamental mechanism of radiotherapy failure, comprehensive studies are warranted to elucidate associated resistance mechanisms and potential adverse effects. Such insights will facilitate the clinical translation of ferroptosis-targeting strategies into optimized radiotherapy paradigms.

Ferroptosis and HTT
HTT, a pivotal physical modality in oncology, selectively ablates malignant tissues by elevating the local temperature to 41–46°C through radiofrequency, microwave, ultrasound, or laser energy sources.[218] However, its therapeutic efficacy is often compromised by the overexpression of HSPs, particularly HSP90, in tumor cells. These proteins stabilize client proteins and form a major clinical barrier to effective treatment. Recent advances have demonstrated that lipid peroxides (LPOs) generated during ferroptosis can effectively degrade HSPs through covalent modification of critical cysteine residues, thereby overcoming tumor thermotolerance.[219] This bidirectional synergy is mechanistically compelling: thermal energy enhances the release of catalytic iron ions, accelerating Fenton reactions, while ferroptotic LPOs simultaneously disrupt HSP cytoprotective networks, amplifying tumor cell thermal sensitivity. Together, this establishes a self-amplifying therapeutic circuit that integrates ferroptosis and hyperthermia.[220] Nanotechnology further propels this synergy. Functionalized nanomaterials not only overcome the pharmacokinetic limitations of conventional FINs but also leverage intrinsic photothermal or magnetic properties, enabling precision spatiotemporal co-delivery of HTT and ferroptosis induction. This convergence establishes a transformative multimodal platform for solid tumor therapeutics.[221]
PTT is an essential branch of hyperthermia technology and, along with MHT, constitutes an emerging physical treatment paradigm for noninvasive, localized tumor therapy. Its core mechanism relies on photothermal conversion agents that efficiently transform photon energy into thermal energy under near-infrared (NIR) laser irradiation through electron-phonon relaxation effects. This process achieves selective tumor ablation by disrupting HSP network and inducing lipid bilayer phase transitions in cell membranes.[222] PTT exhibits distinct clinical potential in precision oncology for solid tumors, owing to its deep tissue penetration capability, real-time fluorescence imaging-guided treatment monitoring, and minimally invasive nature.
Ferrocene (Fc), as an efficient iron donor for Fenton reactions, exhibits thermally responsive properties that can be precisely activated by localized tumor hyperthermia. Elevated temperatures not only directly ablate cancer cells but also enhance Fenton reaction efficiency by accelerating iron ion release. Building on this mechanism, a nanoplatform integrating DiR (a photothermal probe) with Fc enables synchronized photothermal conversion and iron ion liberation under NIR light irradiation, inducing dual-pathway synergistic effects that trigger lipid peroxidation cascades and ultimately achieve potent tumor eradication in BC models.[223] In parallel, manganese dioxide (MnO2) nanomaterials show considerable potential in PTT due to their broad-spectrum light absorption and capacity to modulate tumor hypoxia via H2O2 decomposition.[224] These nanomaterials function through dual mechanisms: depleting GSH to inactivate GPX4 for ferroptosis induction, while concurrently catalyzing hydroxyl radical generation via Fenton chemistry, synergistically amplifying lipid peroxide accumulation.[225] Furthermore, the ferritin-based nanocomposite iron‑oxide nanoparticle@polydopamine with disulfide‑linked ferritin (I@P-ss-FRT), constructed by conjugating iron-storage ferritin to polydopamine-coated iron oxide nanoparticles via disulfide bonds, exhibits multifunctional therapeutic capabilities under NIR irradiation. The localized hyperthermia generated not only directly ablates tumor tissue but also promotes GSH-mediated disulfide bond cleavage to accelerate ferrous ion release. Notably, heat-induced structural relaxation of ferritin subunits enhances reductant permeability into its iron core, establishing a multimodal cooperative strategy that integrates photothermal ablation with ferroptosis activation for overcoming therapy resistance in BC.[226] Interestingly, researchers have recently developed a novel material capable of in situ transforming into Pd@Cu2-xS (termed PCS) within colorectal tumor tissues. Surface Cu+ ions on PCS catalyze Fenton-like reactions with the overexpressed H2O2 in colon tumors. Simultaneously, PCS induces GSH depletion and downregulates the expression of GPX4 under the weakly acidic TME, thereby promoting ferroptosis through multiple mechanisms.[227]
Photothermal nanomaterials integrated with FINs demonstrate enhanced antitumor efficacy through multimodal synergistic mechanisms. For instance, the multifunctional platform PFP@Au-Fe2C-SRF, constructed from iron carbide (Fe2C), combines NIR responsiveness and Fenton catalytic activity while co-encapsulating sorafenib to suppress GPX4 activity, thereby amplifying ferroptosis induction and achieving synergistic tumor inhibition.[228] Moreover, ferrimagnetic vortex-domain iron oxide nanorings exhibit dual functionality by augmenting cellular iron uptake to sensitize HCC cells to sorafenib-induced ferroptosis, while their nanothermal effects concurrently boost ROS accumulation and GPX4 inactivation, establishing a self-reinforcing ferroptosis loop.[229] Furthermore, the Fe3O4 core@mesoporous SiO2 shell with arginine-glycine-aspartic acid (RGD) peptide (FSR)-Fin56 system, based on biocompatible Fe3O4 nanoparticles, disrupts tumor redox homeostasis through dynamic iron cycling—Fe3+-mediated GSH depletion coupled with Fe2+-driven Fenton reactions—and synergizes with Fin56-induced GPX4 degradation to achieve potent ferroptosis-driven tumor suppression in osteosarcoma models. Together, this multimechanistic synergy exemplifies a paradigm-shifting strategy for enhancing cancer therapy through nanomaterial-enabled ferroptosis potentiation.[230]
MHT operates through the generation of localized heat through magnetic nanoparticles (MNPs) under an alternating magnetic field, leveraging hysteresis loss effects to achieve precise thermal ablation of tumors.[218] Emerging evidence indicates that MHT exerts dual antitumor mechanisms by both directly triggering ferroptosis through thermal stress and systematically enhancing tumor cell susceptibility to ferroptosis through the integration of nanocarriers with ferroptosis-inducing agents.
Iron oxide nanoparticles (IONPs) have been widely applied in cancer theranostics due to their capacity to release Fe2+/Fe3+, mediating Fenton reaction-derived ROS for ferroptosis induction. In castration-resistant PC, combining a fatty acid synthase inhibitor (FASNi) with IONP-based biomimetic nanovesicles achieves synergistic ferroptosis enhancement via dual modulation of ROS generation and metabolic tolerance balance.[231] Expanding this strategy, a disulfide-bridged mesoporous nanosystem encapsulating lonidamine (LND) within Fe3O4 nanoparticles has been developed. LND depletes GSH by inhibiting glycolysis, while disulfide bonds disrupt redox homeostasis and inactivate GPX4. Together with mitochondrial dysfunction-induced ROS and lactate accumulation, this combination remodels the acidic TME to promote tumor cell death.[232] Lac-FcMOF is a ferromagnetic metal-organic framework (FcMOF) modified with a lactose derivative (Lac-NH2), which possesses magnetic hyperthermia properties and thermal stability. It accelerates GSH depletion and ∙OH generation through magnetothermal-driven Fc ion-mediated processes, inducing oxidative damage, inhibiting HSP70 synthesis, promoting GPX4 inactivation, and increasing lipid peroxide levels, thereby further enhancing ferroptosis.[220] Moreover, Art-loaded magnetic nanodroplets not only generate ROS via Art–Fe2+ interactions but also elevate intracellular free Fe2+ levels through lysosomal ferritin degradation and TFRC-mediated iron uptake, establishing a self-reinforcing ferroptosis activation pathway.[233] Innovatively, ferrimagnetic nanocubes loaded with the potent FIN RSL3 have been integrated into AAGel, establishing the first hysteresis loss-based sustained-release hydrogel formulation incorporating MNPs. Endogenous AA promotes lipid peroxide accumulation to synergistically enhance RSL3 efficacy, while the nanocubes maintain redox-active iron pool homeostasis via multimodal MHT. This enables continuous ROS/LPOs generation and thermoresponsive acceleration of RSL3 release. The dual-action mechanism reverses tumor thermal resistance through HSP70 degradation while amplifying MHT efficacy via ferroptosis progression, ultimately forming a self-reinforcing feedback loop for therapeutic enhancement.[234]
In summary, hyperthermia enhances tumor cell sensitivity to ferroptosis through multimodal synergistic mechanisms, establishing an innovative therapeutic paradigm for improving oncological outcomes and advancing precision cancer therapy.

Ferroptosis and Immunotherapy
Antitumor therapies have entered the era of immunotherapy, where immune checkpoint blockade (ICB)-based treatment has achieved considerable success. However, their efficacy is significantly limited by low immune response rates, creating an urgent need for new solutions. Growing preclinical evidence has demonstrated that inducing ferroptosis synergistically enhances immunotherapy efficacy, mediated through immunogenic ferroptosis of tumor cells and the activation of immunostimulatory cell populations coupled with suppression of immunosuppressive cell functionality [Figure 4].

Dual role of ferroptosis in the TME
TME is a highly structured ecosystem primarily composed of tumor cells, immune cells, stromal cells, soluble factors, and extracellular matrix. Immune cells mainly include T cells, macrophages, natural killer (NK) cells, dendritic cells (DCs), neutrophils, and myeloid-derived suppressor cells (MDSCs).[235] The intricate crosstalk between tumor cells and tumor-infiltrating immune cells within TME mediated by ferroptosis significantly influences tumor progression and immunotherapy efficacy. For one thing, tumor cells undergoing ferroptosis can modulate antitumor immune responses. For another thing, the susceptibility of immune cells to ferroptosis differs significantly in the TME; consequently, different immune cells in the TME can either promote or suppress tumors under the influence of ferroptosis.

Effect of ferroptotic tumor cells on the immune system
The process by which tumor cells undergo cell death upon external stimulation and transform from non-immunogenic to immunogenic, thereby inducing an antitumor immune response, is called immunogenic cell death (ICD). Tumor cells undergo ICD and produce a series of signaling molecules, known as DAMPs.[236] Many studies have reported that ferroptotic tumor cells release a series of DAMPs as immunostimulatory signals, including high-mobility group box 1 (HMGB1), adenosine triphosphate (ATP), and calreticulin.[237–240] These signals lead to DCs maturation, M1 macrophages polarization, and cytotoxic T-cells infiltration in tumors.[239,241] Ferroptotic tumor cells may even elicit a vaccine-like effect to enhance efficient antitumor immunity. The stage of ferroptotic cells regulates their immunogenic potential and the subsequent antitumor immune activation, although the appropriate stage remains controversial.[242] In one study, only early-stage (3 hours postinduction) but not late-stage (24 hours postinduction) ferroptotic tumor cells could prime DCs’ maturation and activate antitumor immunity.[238] However, it has also been reported that ferroptotic tumor cells fail to elicit immune protection despite the release of DAMPs and cytokines. In addition, early-stage ferroptotic tumor cells impeded DCs’ maturation and negatively affected the antigen-presenting features of DCs, consequently inhibiting antitumor adaptive immunity.[243] Currently, the evidence tends to support that ferroptosis is a type of ICD and ferroptotic tumor cells can promote antitumor immunity,[242] but further research to clarify the relationship between ferroptosis and ICD is necessary.

Ferroptosis in immunostimulatory cells promotes tumor progression
A growing body of evidence supports that the TME is a double-edged sword, and the immunosuppressive TME is a key factor affecting immunotherapy efficacy. Type 1 CD8+ T cells, or cytotoxic T lymphocytes (CTLs), are the main cells that mediate antigen-specific immune responses, and they play a key role in antitumor immunity. Cluster of differentiation 36 (CD36) is a key regulator in lipid metabolism.[244] CD36 promotes lipid peroxidation and induces ferroptosis in CD8+ T cells by facilitating the uptake of fatty acids, particularly AA, resulting in decreased cytotoxic cytokine production and suppressed antitumor immune responses.[245] Furthermore, CD36 mediates oxidized low-density lipoprotein (OxLDL) uptake in CD8+ T cells and induces lipid peroxidation and the phosphorylation of p38, promoting CD8+ T-cell dysfunction.[246] In addition, programmed cell death-1 (PD-1) signaling in CD8+ T cells can also inhibit phospholipid phosphatase 1 (PLPP1) expression and promote ferroptosis of CD8+ T cells, impairing antitumor immunity.[247] NK cells are responsible for immune surveillance against tumors,[248] and it has been reported that NK cells are significantly reduced in the TME of GC.[249] L-kynurenine (L-KYN), produced by tryptophan metabolism within the TME, induces ferroptosis of NK cells. Overexpressing GPX4 in NK cells reverses L-KYN-induced ferroptosis, which may be useful for immunotherapy of GC.[250] DCs are the most powerful APCs.[251] Promoting ferroptosis of tumor-infiltrating DCs inhibits their antitumor function. Lipid peroxidation byproduct 4-hydroxy-trans-2-nonenal (4-HNE) is a marker of ferroptosis. ROS and 4-HNE induce endoplasmic reticulum stress and activate X-box binding protein 1 (XBP1), which regulates lipid metabolism and antigen presentation by tumor-infiltrating DCs, ultimately promoting tumor progression.[252,253]

Ferroptosis resistance in immunosuppressive cells promotes tumor progression
Resistance to ferroptosis by immunosuppressive cells within the TME can also affect the efficacy of immunotherapy, including tumor-associated macrophages (TAMs), MDSCs, and regulatory T cells (Tregs), which can significantly inhibit CTLs infiltration and function, leading to tumor progression. Tumor cells–TAMs crosstalk plays a pivotal role in protecting tumor cells from ferroptosis and facilitating immunotherapy resistance. TAMs are highly plastic and can polarize into M1 (antitumor) or M2 (pro-tumor) phenotypes because of TME changes, with M2 predominating in the TME.[254,255] Tyrosine protein kinase receptor 3 (TYRO3), a receptor tyrosine kinase that is expressed by tumor cells, not only inhibits ferroptosis of tumor cells but also promotes a tumor suppressive microenvironment by upregulating vascular endothelial growth factor (VEGF) and reducing the M1/M2 macrophage ratio, leading to immunotherapy resistance.[256] Ceruloplasmin (CP) is another protein involved in iron release and transport,[257] and a preclinical study showed that M1 TAMs expressed high levels of CP mRNA, which is transferred from TAMs to tumor cells by extracellular vesicles and then translated. CP facilitates iron export, protecting tumor cells from lipid peroxidation and RSL3-induced ferroptosis.[258] TAM-secreted taurine suppresses ferroptosis in PC by activating the liver X receptor α (LXRα)/SCD1 axis. LXRα enhances tumor-derived extracellular vesicle miR-181a-5p expression, which triggers M2 polarization and further taurine release. Targeting the taurine transporter TauT may restore TAM ferroptosis sensitivity, offering a therapeutic strategy.[259] Analogously, annexin A3 (ANXA3), by activating the Akt/glycogen synthase kinase 3β (GSK3β)/β-catenin pathway, may reprogram M2 macrophages, which secrete ANXA3-rich exosomes, to inhibit ferroptosis in laryngeal cancer cells and drive tumor progression.[260] Oxidized phospholipid 1-stearoyl-2-15-HpETE-sn-glycero-3-phosphatidylethanolamine (SAPE-OOH) on ferroptotic cells acts as an “eat me” signal by binding Toll-like receptor 2 (TLR2) on TAMs, mediating the phagocytosis of ferroptotic cells.[261] However, further research demonstrated that in the phospholipid peroxidation of TAMs, SAPE-OOH competitively blocked the interaction between TLR2 and canopy FGF signaling regulator 3 (CNPY3), leading to TLR2 being retained and degraded in the endoplasmic reticulum, impairing TAM phagocytic function, and evoking tumor resistance to ferroptosis therapy.[262]
MDSCs are a heterogeneous array of pathologically activated immature cells with potent immunosuppressive activity that suppress T-cell activity and promote the immune escape of malignant tumors. MDSCs comprise two major groups: polymorphonuclear MDSCs (PMN-MDSCs) and monocytic MDSCs (M-MDSCs).[263] MDSCs’ resistance to ferroptosis in the TME depends on high expression of neutral ceramidase N-acylsphingosine amidohydrolase 2 (ASAH2) which destabilizes p53 and represses the HMOX1 pathway. The ASAH2 inhibitor NC06 increases the stability of the p53 protein, which in turn upregulates HMOX1 expression and enhances the production of lipid ROS, thereby promoting ferroptosis in MDSCs.[264] Compared with M-MDSCs, PMN-MDSCs are more susceptible to ferroptosis and undergo spontaneous cell death in the TME. Mechanistically, increased AA uptake via the fatty acid transport protein 2 (FATP2) and hypoxia-triggered GPX4 downregulation in PMN-MDSCs promote the accumulation of oxidized phosphatidylethanolamine containing AA to drive ferroptosis. However, ferroptosis of PMN-MDSCs releases immunosuppressive molecules, including prostaglandin E2 (PGE2) and oxidized lipids, before cell death to inhibit the antitumor function of T cells.[265]
In chemoresistant BC, tumor-infiltrating neutrophils (TINs) exhibit high ferroptosis sensitivity because of acyltransferase multispecific organic anion transporter 1 (MOAT1) downregulation, which drives phospholipid reprogramming from MUFA to PUFA. Ferroptotic neutrophils release immunosuppressive mediators (PGE2, indoleamine 2,3-dioxygenase, and oxidized lipids) that inhibit CD8+ T-cell function.[266] Aconitate decarboxylase 1 (ACOD1) is highly upregulated in TINs of BC. Activated ACOD1 generates itaconate, which facilitates an NRF2-dependent antioxidant response against ferroptosis and supports the persistence of TINs and tumor progression.[267] TINs also induce tumor cell ferroptosis by delivering myeloperoxidase (MPO)-enriched granules into tumor cells, which causes lipid peroxide accumulation in tumor cells. Interestingly, neutrophil-mediated ferroptosis accelerates tumor necrosis and aggressiveness in glioblastoma progression.[268] Neutrophils are engulfed by tumor cells before granule transfer via integrin-mediated cell adhesion and LC3-associated phagocytosis.[269] The C-X-C motif chemokine ligand 12 (CXCL12)/C-X-C chemokine receptor type 4 (CXCR4) chemotactic pathway has recently been shown to mediate the migration of neutrophils into the tumor and exerts immunosuppressive effects dependent on high ferroptosis tendency and immunosuppressive molecule expression.[270] And ferroptotic intratumoral neutrophils mediated the impairment of T cell anti-tumor immunity. Neutrophil extracellular traps promote tumor cell resistance to ferroptosis and suppress the antitumor function of T cells, thereby contributing to tumor progression.[271,272]
Mast cells are a critical component of myeloid cells. Tumor-infiltrating mast cells (TAMCs) are clinically associated with poor prognosis in PDAC. PDAC cells orchestrate the recruitment of CXCR2-high TAMCs and drive their pathological accumulation within the TME. PDAC cell-derived exosomes safeguard TAMCs against ferroptosis through phosphoinositide 3-kinase (PI3K)/Akt signaling activation. In turn, TAMCs reciprocally enhance PDAC stemness via CXCL10 secretion and recruit CXCR3+ Tregs into the TME, collectively fostering tumor progression and immune evasion. Notably, sodium cromoglicate, a membrane stabilizer for mast cells, increases the therapeutic efficacy of anti-PD-1 combined with gemcitabine by suppressing CXCL10-mediated crosstalk.[273]
Tregs are helper T cells that promote tumor generation and progression by inhibiting antitumor immune responses.[274] Tregs require GPX4 to maintain an activated state by preventing lipid peroxidation and ferroptosis. The absence of GPX4 can induce Tregs ferroptosis and the production of the proinflammatory cytokine IL-1β, which promotes T helper cell 17 (TH17) responses and ultimately antitumor immunity. Targeting GPX4 and ferroptosis in Tregs appears to be a promising immunotherapy strategy.
Cancer-associated fibroblasts (CAFs) promote immune escape and tumor progression by inducing ferroptosis and inhibiting the cytotoxic activity of NK cells. Mechanistically, CAFs export iron into the TME by upregulating the expression of the iron-regulatory genes that encode ferroportin 1 and hephaestin in CAFs, and CAF-derived follistatin-like protein 1 (FSTL1) upregulates nuclear receptor coactivator 4 (NCOA4) expression via the disco interacting protein 2 homolog A (DIP2A)/p38 pathway to mediate ferritinophagy, increasing the LIP and leading to NK-cell ferroptosis.[275] CAFs secrete exosome-derived ALOX15-targeting miR-522 and ACSL4-targeting miR-3173-5p to suppress tumor cell ferroptosis.[276,277] CAFs can also increase ferroptosis resistance in PC cells by secreting cysteine.[278] As a calcium-activated chloride channel protein, the high expression of anoctamin 1 (ANO1) indicates poor immunotherapy efficacy, and ANO1 contributes to immunotherapy resistance by inhibiting tumor cell ferroptosis via activation of the PI3K/Akt signaling pathway and promoting transforming growth factor-β (TGF-β) secretion, subsequently strengthening CAF recruitment and impairing CD8+ T-cell-mediated antitumor immune responses.[279]
Together, these findings reveal that various immune cells in the TME have different sensitivities to ferroptosis, which suggests that the antitumor immune response can be improved by modulating the susceptibility of immune cells to ferroptosis in the TME. A more in-depth exploration of the complex interplay between ferroptosis and immune cells in the TME is needed to provide a new perspective for antitumor immunotherapy strategies.

Boosting immunosurveillance via ferroptosis

Combination strategies: FINs and immunotherapy
Previous studies have shown that low expression of SLC7A11 or high expression of ACSL4 in tumor cells indicates increased sensitivity to ferroptosis and effective immunotherapy. In contrast, high expression of GPX4 indicates resistance to ferroptosis and ineffective immunotherapy. Therefore, the combination of immunotherapy and FINs is a promising therapy[280] [Table 2]. Amino acid metabolism has a unique role in regulating ferroptosis.[281] Methionine participates in GSH production, whose depletion causes ferroptosis.[282] A recent study demonstrated that tumor cation transport regulator homolog 1 (CHAC1) deficiency caused immunotherapy resistance, and intermittent dietary methionine deprivation promoted GSH degradation and facilitated tumor cell ferroptosis by stimulating CHAC1 transcription. Hence, intermittent methionine deprivation also sensitizes tumor cells against CTL-mediated cytotoxicity and reverses immunotherapy resistance.[283] A triple combination of intermittent dietary methionine deprivation, system Xc− inhibitor IKE, and anti-PD-1 showed marked antitumor efficacy, inhibiting tumor growth and improving survival in mice.[283] Some preclinical studies indicate that GPX4 inhibitors, such as RSL3, ML162, and N6F11, can enhance tumor sensitivity to immunotherapy. Ferroptosis stress generates ROS to activate NF-κB and calcium influx to promote programmed cell death-ligand (PD-L1) expression. High PD-L1 expression on tumor cells, which is a mechanism for immune evasion, also renders them more susceptible to immunotherapy. A combination of GPX4 inhibitors and ICB constitutes a potentially effective therapeutic strategy.[284,285] N6F11 specifically causes tumor cell ferroptosis, without affecting the survival of immune cells.[286] A recent study also revealed that ferroptosis of tumor cells was evaded via upregulation of GPX4 during metastatic progression of GC, and a GPX4 inhibitor enhanced the efficacy of chimeric antigen receptor T (CAR-T) cell therapy.[287] Cisplatin, a chemotherapy drug and FIN, has been reported to induce ferroptosis of tumor cells while also polarizing neutrophils and promoting T-cell infiltration and Th1 differentiation, thereby enhancing the efficacy of immunotherapy.[288] Lovastatin, a type of statin, can not only induce ferroptosis in NSCLC cells but can also inhibit PD-L1 expression, reshaping immuno-cold tumors to immuno-hot tumors.[289] In addition, mefloquine, a novel FIN, enhances the efficacy of anti-PD-1 immunotherapy by activating interferon (IFN)-γ/STAT1/IRF1/lysophosphatidylcholine acyltransferase 3 (LPCAT3)-induced ferroptosis in tumors.[290] Except for traditional FINs, other therapeutic strategies targeting tumor cell ferroptosis are also the focus of attention. Inhibition of phosphoglycerate mutase 1 (PGAM1) promoted HCC cell ferroptosis and CD8+ T-cell infiltration by downregulating LCN2 and PD-L1. The PGAM1 inhibitor KH3 shows potent antitumor effects and can synergize with anti-PD-1 immunotherapy in HCC.[291] Similarly, mitochondrial translocator protein (TSPO) facilitates immune escape by inhibiting ferroptosis and increasing PD-L1 expression in HCC cells through the activation of an NRF2-dependent antioxidant defense system. The TSPO inhibitor PK11195 synergizes with anti-PD-1 to produce antitumor effects in mouse models.[292] Aberrantly activated PI3K and dysregulated histone deacetylase (HDAC) are two well-established targets for cancer therapy. BEBT-908, a dual-target PI3K and HDAC inhibitor, promotes immunogenic ferroptosis in tumor cells via p53 hyperacetylation, further inducing major histocompatibility complex class I (MHC I) upregulation and activating IFN-γ signaling, thereby promoting a proinflammatory TME and enhancing ICB therapy.[293]

Modulating ferroptosis sensitivity in immune cells to enhance immunotherapy
Ferroptosis is associated with T-cell immunity and tumor immunotherapy. Activated CD8+ T cells can secrete the cytotoxic cytokines IFN-γ and tumor necrosis factor (TNF)-α to indirectly kill tumor cells. IFN-γ released by CD8+ T cells mediates the downregulation of solute carrier family 3 member 2 (SLC3A2) and SLC7A11 expression to inhibit cystine uptake, thereby promoting lipid peroxidation and tumor cell ferroptosis. Cyst(e)inase, a synthetic enzyme to degrade both cystine and cysteine, can induce tumor cell ferroptosis and antitumor immunity.[294] IFN-γ synergizes with AA to induce lipid ROS production and ferroptosis in tumor cells, which is mediated by IFN-γ promoting ACSL4 upregulation via STAT1 and IRF1 signaling without a synthetic FIN and results in AA integration into phospholipids.[295] Thus, it may be a natural endogenous ferroptosis mechanism. The combination of anti-PD-L1 therapy with cyst(e)inase or AA markedly boosts antitumor immunity, leading to greater tumor suppression than a single therapy.[294,295] It has also been reported that adoptively transferred tumor-specific type 9 CD8+ T (Tc9) cells show a stronger antitumor activity and express lower levels of cholesterol.[296] IL-9 secreted from Tc9 cells may activate STAT3 and increase fatty acid oxidation, leading to a decrease in lipid peroxidation and ROS-induced ferroptosis in Tc9 cells.[297] These findings indicate that inhibiting ferroptosis in CD8+ T cells can strengthen antitumor immunity. In addition, the combination of anti-FSTL1 and deferoxamine significantly inhibits NK cell ferroptosis.[275] As mentioned earlier, reversing the ferroptosis resistance of immunosuppressive cells may improve tumor immunotherapy and provide a new strategy for combined immunotherapy. M1 macrophages exhibit higher levels of inducible NO synthase (iNOS) and NO· compared with M2 macrophages. iNOS/NO· expression inhibits ALOX15-mediated lipid peroxidation and ferroptosis, leading to high resistance of M1 macrophages and high sensitivity of M2 macrophages to ferroptosis.[298] Therefore, a chiral ruthenium nanozyme (D/L-Arginine@Ru) was engineered to produce NO· and ROS through a self-autocatalytic cascade reaction to induce M1 polarization and reverse tumor immunosuppression.[299]

Nanotechnology-powered FINs
Currently, nanotechnology is also extensively applied to the development of FINs, which can improve water solubility and metabolic stability, and combination with immunotherapy can further suppress tumor progression and improve therapeutic efficacy.[300–302] An injectable and in situ cross-linked hydrogel system based on chitosan hydrochloride and oxidized dextran (CH-OD) was designed.[303] Intraperitoneal injection of SSZ-loaded CH-OD (CH-OD-SSZ) hydrogel sustains effective SSZ concentrations, induces higher levels of immunogenic ferroptosis, and effectively reduces ascites in the mice model of hepatoma ascites. Furthermore, CH-OD-SSZ induced macrophage polarization from M2 to M1 phenotype and promoted DCs maturation and activation in vitro. The expression of PD-L1 on tumor cells was also significantly upregulated. Combining CH-OD-SSZ with anti-PD-L1 therapy significantly suppressed tumor growth and improved mice survival. Similarly, SSZ-loaded platelet membrane-camouflaged MNPs (Fe3O4) have also been shown to trigger ferroptosis and enhance cancer immunotherapy.[304] In another example, an iron-based metal-organic framework nanoreactor loaded with dihydroartemisinin (DHA@MIL-101) was developed to activate ferroptosis in TAM and convert TAM to the M1 phenotype to exert an antitumor effect.[305] In addition, as a novel biomimetic FIN, D@FMN-M has been reported to promote dual ferroptosis in both tumor cells and M2 macrophages, thereby enhancing tumor immunotherapy.[306]
Together, these findings systematically reveal the dynamic regulatory role of ferroptosis-mediated lipid peroxidation metabolic reprogramming in the TME. They further demonstrate that targeting ferroptosis enhances immunotherapy efficacy and elucidate the effectiveness of combining immunotherapy with FINs. This not only provides a theoretical foundation for immunotherapeutic strategies based on the ferroptosis mechanism but also offers new antitumor combination strategies.

Clinical Trials of FINs for Antitumor Therapy
As a distinct form of programmed cell death, ferroptosis has significant therapeutic potential in tumor treatment. Substantial evidence has accumulated from preclinical studies, thus necessitating clinical translation through clinical trials for validation. Besides the antitumor drugs that induce ferroptosis and are used clinically, such as sorafenib, lapatinib, cisplatin, and gemcitabine, other FINs are in phase I–II clinical trials as antitumor drugs.
SSZ is a radiosensitizer because of its ferroptosis-inducing effect and is currently in a phase I trial (NCT04205357) to evaluate the safety of adding SSZ to stereotactic radiosurgery for recurrent glioblastoma. However, a previous phase I/II trial of SSZ for the treatment of progressive malignant glioma was terminated prematurely because of the lack of efficacy and serious neurological adverse events.[307] A phase II clinical trial of SSZ to relieve chronic pain in patients with BC has also been completed (NCT03847311). A phase 3 clinical trial evaluating the potential efficacy and safety of SSZ in patients with metastatic CRC and a phase I/II trial in newly diagnosed patients with acute myeloid leukemia are recruiting patients (NCT06134388, NCT05580861). Whether SSZ ultimately has antitumor effects requires further clinical trial research. A previous phase I clinical trial showed that oral artesunate at doses up to 200 mg per day as add-on therapy was safe and well tolerated in patients with metastatic BC (NCT00764036).[308] A phase II clinical trial evaluating the safety and effectiveness of preoperative artesunate before surgery in patients with stage II/III CRC is in progress (NCT02633098). Several other completed phase I clinical trials have shown that artesunate is well tolerated, including intravaginal artesunate for the treatment of HPV+ high-grade cervical intraepithelial neoplasia (NCT02354534) and intra-anal administration of artesunate in patients with high-grade anal intraepithelial neoplasia (NCT03100045). The maximum tolerated dose of intravenous artesunate in the treatment of advanced solid tumors was 18 mg/kg (NCT02353026).[309] However, the effectiveness of artesunate needs further evaluation. Statins have also been used in clinical trials for antitumor treatment, and their combination with standard tumor treatments can improve efficacy. Fluvastatin and atorvastatin inhibited tumor growth in two perioperative window trials for BC.[310,311] Another pilot window-of-opportunity trial of atorvastatin in p53-mutant and p53-wild-type malignancies is in progress (NCT03560882).
It is essential to advance ferroptosis-targeted therapeutic strategies from preclinical to clinical application, so strict and large-scale clinical trials are needed to evaluate the safety and efficacy of ferroptosis-targeted drugs.

Conclusions and Perspectives
Ferroptosis is a distinct form of regulated cell death characterized by iron-dependent lipid peroxidation, which leads to irreversible damage to cellular membrane systems. The conceptualization of ferroptosis marked a significant milestone in the field of cell biology. With the rapid development of related research, the multifaceted roles of ferroptosis in tumor biology have been progressively elucidated. Accumulating evidence demonstrates that ferroptosis plays a complex regulatory role in the initiation and progression of cancer. Furthermore, ferroptosis resistance is increasingly recognized as a key mediator of resistance mechanisms in clinical cancer therapies.
This review begins by elucidating the inherent double-edged sword role of ferroptosis in cancer therapeutics. Although ferroptosis induction can suppress tumor progression, malignant cells may exploit ferroptotic mechanisms to evade immune surveillance or escape treatment eradication. Building on this rationale, we subsequently highlight the promise of synergistically integrating FINs with established treatment modalities–including chemotherapy, radiotherapy, and targeted therapies–highlighting its capacity to overcome resistance in therapeutically recalcitrant tumors. Finally, we comprehensively assess the current clinical landscape of ferroptosis-targeting paradigms in ongoing cancer trials.
The common resistance nodes associated with ferroptosis in conventional anticancer therapies primarily manifest as the compensatory activation of antioxidant pathways, dynamic sequestration of intracellular iron, and enhanced clearance of lipid peroxides. Regarding the antioxidant defense, standard treatments often induce the upregulation of SLC7A11 and GPX4, which act to neutralize lipid peroxidation. Disruption of iron homeostasis in resistant tumor cells is characterized by the downregulation of HMOX1 and abnormal accumulation of ferritin (FTL/FTH1), which sequesters free iron, along with suppressed iron uptake through TFRC. Together, these changes effectively inhibit lipid peroxidation driven by the Fenton reaction. In addition, some resistant tumor cells suppress the expression of lipid metabolism enzymes, such as SCD1 and ACSL4, thereby directly limiting the production of lipid peroxides and preventing ferroptosis. These ferroptosis-related resistance mechanisms serve as central regulatory hubs across multiple treatment modalities, including chemotherapy, radiotherapy, and immunotherapy. Not only do they form critical barriers to conventional therapies, but they also represent potential points of vulnerability that can be exploited for therapeutic synergy. FINs exert antitumor effects by targeting antioxidant systems, such as GPX4 and SLC7A11, to promote ferroptotic cell death. In combination therapies, FINs targeting the antioxidant axis, when used alongside platinum- or taxane-based chemotherapy or precision radiotherapy, can disrupt compensatory antioxidant responses, thereby resensitizing tumor cells. These strategies not only reverse resistance to chemo- and radiotherapy but also enhance tumor immunogenicity, achieving dual therapeutic benefits. Given their applicability across cancer types, targeting shared ferroptosis resistance nodes presents a promising strategy to overcome the limitations of conventional treatments, enabling synergism with chemotherapy, immunotherapy, and radiotherapy through the release of DAMPs.
We then discuss how advances in nanotechnology have facilitated the integration of HTT with ferroptosis, enabling tumor-specific and precise eradication of solid malignancies through spatiotemporally controlled thermal activation and iron-mediated lipid peroxidation. This synergy has redefined therapeutic paradigms for solid tumor treatment. In the field of immunotherapy, ferroptosis can also induce ICD, leading to the release of DAMPs, activation of DCs, and enhancement of T-cell responses, thereby synergizing with ICB. These insights underscore the significant therapeutic potential of pharmacological strategies targeting ferroptosis as an emerging approach to cancer treatment. However, realizing the clinical potential of ferroptosis-targeted therapies will require overcoming several challenges in future research. A pressing issue is the identification of predictive biomarkers to enable patient stratification. This involves defining and validating subpopulations with heightened sensitivity to ferroptosis based on evidence from cell lines and preclinical studies, thereby guiding precision treatment. Specifically, this challenge encompasses two major research directions: first, the development of reliable detection tools to quantitatively assess ferroptosis-related markers in biofluids or tissue samples, including expression levels of key molecules, such as ACSL4, SLC7A11, and GPX4, as well as the abundance of PUFA-PLs; second, the integration of multi-omics approaches, such as single-cell omics, spatial transcriptomics, proteomics, and metabolomics, to conduct systematic evaluations. Leveraging artificial intelligence to build large-scale databases may further improve predictions and enable comprehensive profiling of ferroptosis susceptibility across populations. However, the development of tumor-selective FINs remains a major bottleneck. The mechanisms and strategies to achieve selective induction or inhibition of ferroptosis in specific tissues, cell types, or disease contexts are still poorly defined. This selectivity is a decisive factor for clinical translation. For example, systemic inhibition of GPX4 is associated with significant toxicities, including renal and cardiac injury, highlighting the need to optimize targeted delivery, improve pharmacokinetics and biodistribution, and identify context-specific ferroptosis regulators, which should be future priorities in drug development. Last, the role of ferroptosis within the tumor immune microenvironment is marked by complex bidirectional regulation. On one hand, ferroptosis-induced ICD can enhance antitumor immunity; on the other, ferroptosis may exert cytotoxic effects on immune cells, such as T cells and DCs, necessitating a precise understanding of the differential sensitivity between cancer and immune cells. Furthermore, LPOs released during ferroptosis, such as malondialdehyde and 4-HNE, may drive either proinflammatory or immunosuppressive responses, depending on the tumor context. The molecular mechanisms underlying the crosstalk between ferroptosis and immune checkpoint signaling pathways, such as PD-L1/PD-1, remain incompletely understood, posing significant challenges for the rational design of combination therapies. To address these limitations, combinatorial strategies are required, such as integrating ferroptosis modulation with immunotherapy or nanotechnology-based delivery systems, to enhance therapeutic specificity and overcome barriers within the tumor stroma.
Although ferroptosis-mediated antitumor therapy has entered the early stages of clinical exploration, it continues to face significant challenges, including safety, efficacy, and drug resistance. Overcoming these challenges requires multidisciplinary collaboration and validation through strict and large-scale clinical trials. With the emergence of improved FINs and optimized combination strategies, ferroptosis-inducing therapy is expected to become an important part of comprehensive tumor treatment in the future, providing new hope for drug-resistant tumors.

Funding
This work was supported by the National Key Research and Development Program of China Stem Cell and Translational Research (No. 2023YFC3402100), the National Natural Science Foundation of China (Nos. 92259102 and 82203331), the Sichuan Province Natural Science Foundation Key Project (No. 2024NSFSC0057), and the Major Project of Chongqing Natural Science Foundation (No. CSTB2024TIAD-KPX0029).

Conflicts of interest
None.