IL-1 signaling and inflammasomes in acute myeloid leukemia: mechanisms and therapeutic opportunities.

Acute myeloid leukemia
Acute myeloid leukemia (AML) is a clonal malignancy of hematopoietic progenitor cells, characterized by the accumulation of immature myeloid blasts in the bone marrow (BM) and peripheral blood (PB), leading to ineffective hematopoiesis and BM failure. Clinically, the disease typically presents with fatigue, bleeding, infections, and cytopenias. Diagnostic approaches, risk stratification, and treatment strategies have evolved considerably in recent years, particularly following the 2022 World Health Organization (WHO) classification and the updated European LeukemiaNet guidelines (ELN). The WHO 2022 revision reflects a shift from morphology-based to genomics-driven diagnostics. When specific genetic abnormalities are present, such as: t(8;21)(q22;q22.1); RUNX1::RUNX1T1; inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB::MYH11; t(15;17)(q24.1;q21.2); PML::RARA, the threshold of ≥ 20% myeloid blasts in peripheral blood or BM is no longer required for diagnosis of AML.
AML is now categorized into the following major groups: (1) AML with recurrent genetic abnormalities; (2) AML with mutated genes (e.g., NPM1, CEBPA, RUNX1), (3) AML with myelodysplasia-related gene mutations or cytogenetic changes, (4) therapy-related myeloid neoplasms, and (5) AML not otherwise specified (NOS). Notably, AML with myelodysplasia-related changes (AML-MRC) has been redefined as AML with myelodysplasia-related gene mutations, including mutations in genes such as ASXL1, SRSF2, U2AF1, and TP53. This molecularly oriented approach aligns with the International Consensus Classification [1] and improves the clinical relevance of diagnosis and prognosis.
Accurate risk stratification is essential to guide therapeutic intensity and post-remission strategies. The 2022 ELN classification stratifies AML into favorable, intermediate, and adverse risk categories based on cytogenetic and molecular features [2]. Favorable risk AML include t(8;21)(q22;q22.1)/RUNX1::RUNX1T1, inv(16)(p13.1q22) or t(16;16)(p13.1;q22)/CBFB::MYH11, mutated NPM1 without FLT3-ITD mutation, bZIP in-frame mutated CEBPA. Intermediate risk AML are defined by mutated NPM1 with FLT3-ITD mutation, wild-type NPM1 with FLT3-ITD (without adverse-risk genetic lesions), t(9;11)(p21.3;q23.3)/MLLT3::KMT2A, cytogenetic and/or molecular abnormalities not classified as favorable or adverse. Adverse risk patients include those with t(6;9)(p23.3;q34.1)/DEK::NUP214, t(v;11q23.3)/KMT2A-rearranged, t(9;22)(q34.1;q11.2)/BCR::ABL1, t(8;16)(p11.2;p13.3)/KAT6A::CREBBP, inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2)/GATA2, MECOM(EVI1), t(3q26.2;v)/MECOM(EVI1)-rearranged, −5 or del(5q); −7; −17/abn(17p), complex karyotype, monosomal karyotype, mutated ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, and/or ZRSR2, mutated TP53.
This risk classification informs clinical decisions, particularly regarding the indication for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first complete remission. Treatment decisions depend on patient age, fitness, risk profile, and measurable residual disease status following first line treatment. Fit patients typically receive intensive induction chemotherapy [“7 + 3”: cytarabine for 7 days and anthracycline (e.g., daunorubicin for 3 days) followed by risk-adapted post-remission therapies: favorable risk patients undergo consolidation with high-dose cytarabine, while allo-HSCT is preferred for those in the intermediate or adverse risk categories.
Advances in genomics have led to the integration of targeted therapies. For FLT3-mutated AML, midostaurin is added during induction and consolidation [3]. Patients with IDH1/2 mutations benefit from treatments incorporating ivosidenib and enasidenib, respectively, effective in both newly diagnosed and relapsed/refractory AML [4]. Of note, TP53-mutated AML remains an unmet medical need, as these patients respond poorly to standard regimens; experimental therapies are currently under investigation for this subset.
For patients ineligible for intensive chemotherapy due to age or comorbidities, low-intensity regimens are commonly used. The combination of the hypomethylating agent azacitidine and the BCL-2 inhibitor venetoclax has become a standard of care due to high response rates and improved survival [5]. Additionally, oral azacitidine (CC-486) has demonstrated the ability to prolong overall survival in older patients in remission who are ineligible for allo-HSCT [6], highlighting a shift toward maintenance strategies even outside transplant settings.
Despite these advances, primary refractory diseases (failure to achieve complete remission) and post remission relapses remain a major treatment challenge, affecting approximately 40–50% of AML patients. Relapse is associated with poor prognosis and is often driven by resistant leukemic clones that survive initial therapy. Common persistent mutations include NPM1, DNMT3A, and TET2, while relapse-specific mutations often affect signaling pathways (e.g., FLT3, RAS) and epigenetic regulators.
Prognosis and treatment choices at relapse depend on the duration of initial remission, cytogenetic/molecular profile, patient fitness, and prior treatments. Standard options for relapsed AML include intensive salvage chemotherapy (e.g., FLAG-IDA), targeted agents (e.g., gilteritinib for FLT3-mutated AML, enasidenib or ivosidenib for IDH2/IDH1-mutated AML), and allo-HSCT, which remains the only curative option for eligible patients. In older or unfit patients, hypomethylating agents with venetoclax or low-intensity regimens are used, though remission is often temporary. Emerging therapies, including menin inhibitors and immunotherapies (e.g., bispecific antibodies, CAR-T cells), are under active investigation. Supportive care, including transfusions and infection management, is essential throughout treatment.
Recent advances in genomics have improved understanding of AML relapse mechanisms, paving the way for more personalized therapies. Nevertheless, long-term survival for relapsed/refractory AML patients remains below 20%, underscoring the urgent need for innovative treatment approaches [7, 8].
Beyond genetic aberrations, the BM microenvironment plays a crucial role in AML pathobiology. Historical evidence showing that leukemia-initiating cells can only be maintained in vitro in the presence of stromal cells underscores the importance of external elements within a specialized niche in sustaining leukemia [9]. The BM constitutes a supportive “biome” where multiple cell types are tightly interconnected with leukemic stem cells (LSC), a quiescent reservoir of the leukemic clone poised to drive relapse. LSC co-evolve with surrounding bystander cells in the BM niche, creating a protective microenvironment that promotes survival and immune evasion. Various cell types, including, but not limited to, mesenchymal stromal cells, endothelial cells, osteoblasts, and accessory cells such as macrophages and T lymphocytes, interact dynamically through cytokines, extracellular vesicles and adhesion molecules (as reviewed in [10–13]). Targeting the AML niche is emerging as a complementary therapeutic approach aimed at eradicating residual malignant clones and preventing relapse [14, 15].
Among the inflammatory signals influencing disease progression, whether by acting directly onto the AML blasts or by modulating the niche, interleukin-1 (IL-1) exerts a prominent role [16–18]. IL-1 can inhibit the expansion of normal hematopoietic cells while simultaneously favoring AML progression acting on the BM niche [19, 20]. Myeloid cells are the primary source of IL-1, and AML is no exception; elevated IL-1 levels have been detected in both the BM and the PB of AML patients [21, 22].

IL-1 signaling
IL-1 refers to the product of two independent genes namely IL-1α and IL-1β. They share limited sequence homology (below 30% at the protein level across species), but both bind specifically to the same surface receptor, leading to a strong inflammatory signal. A third ligand included in this family, due to its structure similarity, is the IL-1 receptor antagonist (IL-1RA or IL-1RN). It binds to the same receptor with an affinity even higher than that of the agonists but does not induce downstream signaling, instead functioning as an inhibitor (Fig. 1) [23].
These IL-1 family cytokines bind to a unique transmembrane signaling complex on the cell membrane composed of the IL-1 receptor type I (IL-1R1) and the IL-1R accessory protein (IL-1RAP or IL-1RAcP or IL-1R3). These type I transmembrane proteins hold an intracellular amino-terminal portion and an extracellular carboxy-terminal portion characterized by distinct conserved domains: the TIR domain and Ig-like domains respectively. The TIR domain is conserved among the Toll family, the interleukin-1 receptor family, and the resistance protein encoded by the plant N-gene that confers resistance to tobacco mosaic virus [24]. IL-1α or IL-1β bind to IL-1R1 with high affinity and a 1:1 stoichiometry. IL-1RAP does not interact directly with the ligands but associates with the IL-1R1/IL-1 dimer, forming a ternary structure that brings the cytoplasmic TIR domains of IL-1R1 and IL-1RAP into proximity to recruit and activate downstream signaling molecules. When the antagonistic IL-1RA binds to IL-1R1, it competes with IL-1α and IL-1β and induces conformational changes that prevent IL-1RAP recruitment [25].
The TIR domain recruits proximal signaling adapters via homotypic interactions with intracellular mediators containing a similar structure. When IL-1 binds to IL-1R1, IL-1RAP is recruited, enabling the complex to engage the adaptor molecule MyD88. This interaction promotes the aggregation of IL-1R associated kinases (IRAKs), again via homotypic contacts between their respective death domains. IRAK4 is considered the most upstream enzyme in this cascade; it can self-activate and activate IRAK1 through homodimerization or oligomerization followed by cross-phosphorylation at specific serine/threonine residues. IRAK2 lacks key aspartic acid residues in its kinase domain and was long considered a pseudokinase with adapter-like functions. However, recent reports suggest it possesses a unique, atypical kinase activity. Conversely, IRAK3 lacks catalytic activity and functions as a negative regulator [26].
Another layer of negative regulation of the IL-1 signaling is mediated by the type II IL-1R (IL-1R2) and IL-1R8 [27]. IL-1R2 shares sequence similarity with IL-1R1 in its extracellular ligand-binding domain but lacks a cytoplasmic signaling domain, thus acting as a decoy receptor that sequesters ligands and prevents their engagement with the active receptor complex. Although IL-1R2 can recruit IL-1RAP, this complex is signaling-incompetent. Moreover, IL-1R2 can be cleaved from the cell membrane and released into the circulation, where it neutralizes circulating IL-1. When soluble IL-1R2 associates with the soluble isoform of IL-1RAP, its affinity for IL-1, though not for IL-1RA, increases further [25, 28].
IL-1R8, also known as TIR8 or SIGIRR (Single Ig and TIR domain containing receptor), has a short extracellular domain that cannot directly bind IL-1 family members. Nevertheless, it negatively regulates the IL-1R complex as well as other IL-1R-like and Toll-like receptors. IL-1R8 may sequester proximal signaling molecules from active receptor complexes or interfere with the extracellular portions of the receptors. In addition, IL-1R8 acts as co-receptor for the human anti-inflammatory cytokine IL-37 [27, 28].
A cascade of phosphorylation and aggregation events transmits the inflammatory signal from the IRAKs to key transcription factors. TRAF6, an E3 ubiquitin ligase, is recruited and oligomerized by IRAKs, to trigger the activation of downstream kinases such as MAPK and IKK, which eventually activate AP1 and NF-κB, respectively. NF-κB activation occurs following phosphorylation and degradation of its inhibitory IκB, unleashing the p65 subunit to translocate into the nucleus and initiate a first wave of inflammatory gene expression [29, 30].

IL-1 signaling and targeting in AML
The functional role of IL-1 in modulating AML cell biology was first described in 1987 using IL-1α or IL-1β recombinant proteins and patients samples in vitro [31]. IL-1 was originally proposed to act as an autocrine growth factor inducing proliferation and clonogenicity, as demonstrated by blockade with anti-IL-1 antibodies [32, 33], IL-1RA [34, 35], and soluble IL-1R [36]; induction of—and synergy with—GM-CSF was proposed as the molecular circuit involved [37–42].
Mechanistically, genetic manipulation in mouse models has shown that loss of IL-1RA can favor AML progression in the presence of a preleukemic lesion by inducing myeloproliferation [43]. Accordingly, another study demonstrated that IL-1 exposure fosters the persistence of CEBPA-deficient progenitors. CEBPA a key transcription factor driving myeloid differentiation, is frequently mutated or repressed in AML. In mouse models, deletion of Cebpa in hematopoietic stem cells leads to the accumulation of multipotent progenitors that resist IL-1-induced differentiation and outcompete normal cells, supporting an IL-1-dependent mechanism of oncogenesis, particularly in “CEBPA-low/mutant” AML [44]. Moreover, IDH mutations have been associated with an enhanced IL-1 response in vitro [45]. IDH1/2 gain of function mutations, present in up ot 20% of AML cases, drive the production of oncometabolites and epigenetic reprogramming. In addition, IL-1 signaling is more active in IDH-mutant cells through NF-κB, and inhibition of this pathway shows therapeutic potential in this AML subset [45].
The evidence that low levels of IL-1RA mRNA or higher levels of IL-1β have prognostic value for reduced survival in patients with AML provides a mechanistic rationale for targeting this axis [21, 33, 43]. Recent studies in AML xenograft mouse models using clinical grade anti-IL-1 antibodies (e.g., Canakinumab) or recombinant IL-1RA (i.e., Anakinra) demonstrated preclinical activity [43].
Mirroring the history of IL-1 signaling pathway elucidation in normal cells, several studies have focused on these same biochemical cascades in AML cell lines and leukemic blasts: classical IL-1-mediated signaling activation was confirmed, including MAPK activation and NF-κB translocation, as demonstrated by the use of specific inhibitors in vitro (BIRB-796 or Resveratrol and BAY11-7082, respectively) [46–48]. Notably, these inhibitors not only blocked proliferation but also induced apoptosis. More recently, a specific histone chaperone pathway has been implicated in IL-1-mediated leukemia progression [49]. The histone chaperone ASF1 is upregulated after IL-1 treatment, and both ASF1 and its upstream kinase TLK are overexpressed in several AML subtypes, suggesting that this axis may represent a potential novel therapeutic target across a broad spectrum of patients [49].
Deeper investigation into molecular mechanisms using novel technological approaches led to the identification and functional characterization of specific proteins of the IL-1R complex in AML. In particular, IL-1RAP and IRAK kinases have been scrutinized as novel key regulators and putative targets (Fig. 1).
IL-1RAP mRNA emerged among 11 genes as one of the most significantly upregulated in stem and progenitor cells isolated from patients with different AML subtypes, as compared to age-matched healthy controls [50]. IL-1RAP overexpression correlated with a leukemic granulocytes-monocyte progenitor cell signature [20]. A recent report focusing on normal-karyotype triple-mutated AML (mutations in NMP1, FLT3-ITD and DNMT3A genes) showed upregulation of IL-1RAP in this difficult-to-eradicate AML subgroup [51]. Moreover, higher levels of IL-1RAP mRNA in mononuclear cells from AML patients correlated with adverse outcome [50, 51]. Accordingly, AML samples exhibited higher levels of IL-1RAP protein on the cell surface, correlating with increased sensitivity to IL-1 treatment in vitro [46, 50, 52]. However, the expression pattern of the inhibitory receptors IL-1R2 and IL-1R8 deserves further investigation, as they may dampen responsiveness to IL-1 (Fig. 1). Recent evidence suggests that IL-1R2 mRNA is downregulated in CD34+ AML cells [20].
Knock-down analyses demonstrated that IL-1RAP is not only overexpressed but also required for AML colony formation and cell viability (but not proliferation), supporting its role as a potential therapeutic target [20, 50]. Several antibodies directed against IL-1RAP have been produced and validated for their ability to inhibit AML cells function in vitro and reduce AML growth in mouse models. Mechanistically, these antibodies may block signaling, increase antibody-dependent cellular cytotoxicity, or engage T cells [52–54]. Interestingly, IL-1RAP blockade also affects FLT3 signaling, although it does not overcome constitutive activation of FLT3 mutations [55]. This effect is explained by a physical interaction between IL-1RAP and FLT3, suggests an additional role for IL-1RAP beyond IL-1 signaling in amplifying oncogenic FLT3 signaling [55]. Accordingly, the therapeutic effect of anti-IL1RAP in vitro was stronger than IL-1RA [55].
Notably, antibody-mediated internalization of IL-1RAP in vitro further supports its potential as an immunotherapeutic target [51]. Collectively, these findings highlight a cell intrinsic role of IL-1RAP in malignant cells. However, emerging evidence suggests that the IL-1-IL-1RAP axis may exert an even more prominent role within the leukemic microenvironment [20]. Specifically, IL-1RAP is also expressed by stromal cells, where it mediates IL-1-induced signaling that fosters an inflammatory milieu impairing normal hematopoiesis while sparing AML cells, thereby conferring them a competitive growth advantage [20].
Given the central role of IRAK kinases in IL-1-mediated inflammatory signaling, several IRAK inhibitors have been tested in preclinical AML models. Pacritinib, in addition to being a JAK and FLT3 inhibitor, also shows repressive activity against IRAK1. It was the first compound shown to block the growth of AML cell lines and primary samples in vitro and in xenograft models [56]. Specific FLT3 or JAK inhibitors were less effective under the same in vitro experimental conditions, supporting the relevance of IRAK1 inhibition in AML [56]. Interestingly, treatment of AML cells with FLT3-specific inhibitors resulted in rapid “adaptive resistance” due to TLR9 overexpression and IRAK1/4 activation; optimization of a novel dual FLT3-IRAK1/4 inhibitor (NCGC1481) overcomes this adaptation in vitro and in mouse models, offering new therapeutic perspectives [57]. The selective IRAK4 and FLT3 inhibitor CA4948 (Emavusertib) exerted therapeutic activity in vitro across major AML subtypes, especially in FLT3-mutant samples and when combined with different BH3 mimetics apoptosis inducers [58]. To note, CA4948 reduced the clonogenic potential of AML cells while sparing normal CD34+ stem and progenitor cells in vitro and in mouse xenografts. Additionally, CA4948 induced a monocytic differentiation shift [59]. Although it remains difficult to disentangle the exact relevance of IRAK inhibition from that of FLT3 targeting, CA4948 showed greater efficacy in AML samples harboring splicing factor mutations. This enhanced response correlated with the expression of the canonical long active isoform of IRAK4 compared to the shorter form [59].
Dual targeting of IRAK1 and IRAK4 by genetic deletion or using the novel dual inhibitor KME-2780 was more effective than single targeting in suppressing leukemic stem/progenitor cells function [60]. Along these lines, it was recently proposed that the novel dual IRAK1/4 inhibitory drug UR241-2 can target leukemia stem cells after relapse [61]. Interestingly, the effects of IRAK deletion could not be recapitulated by loss of the upstream adaptor MyD88, suggesting that these kinases may exert MyD88-independent functions in AML deserving further investigation [60].
Overall, these data suggest that IRAK1 and IRAK4 are required to maintain the immature state of leukemia stem/progenitors, and that targeting these kinases may complement current therapeutic approaches.

New IL-1 targeting therapies in AML
In a recent trial involving AML patients in first complete remission and treated with immunotherapy for remission maintenance, Grauers and colleagues measured IL‑1β and endogenous IL‑1RA levels. They observed that low IL‑1β and high IL‑1RA levels during treatment correlated with reduced relapse and improved survival. The treatment regimen itself lowered serum IL‑1β, indicating indirect modulation of IL‑1 pathways. While this does not represent a direct IL‑1 blockade, it highlights the role of IL‑1 in relapse biology [62].
Given the importance of the IL-1 signaling pathways in AML development and progression, and the promising preclinical data, it is not surprising that several IL-1 targeting approaches have reached the clinical arena in the context of interventional trials. The first clinical phase 1 study was performed in patients with relapsed or refractory AML in 1999: treatment with a recombinant soluble IL-1R demonstrated safety but did not show any clinical effect at the administered dose [63].
More recently, cell immunotherapy is being tested. CAR-T medicinal products directed against IL-1RAcP were recently examined in France in 86 AML patients (both adults and pediatric) (NCT04169022). Previous work by the same group demonstrated preclinical efficacy and optimized CAR-T-cells production using a semi-automated system [64–66].
Moreover, the small molecule drug CA-4948 [67], which shows potent inhibitory activity towards both IRAK4 and FLT3, is being tested as monotherapy in adult patients with AML or myelodysplastic syndromes (MDS). A multicenter, open-label, phase 1/2a dose escalation/expansion study was initiated in 2019 [68](NCT04278768).
Finally, Canakinumab (an anti-IL-1β antibody) is being tested in MDS in a phase 2 clinical trial (NCT04239157). Results from this study are not yet available.

Inflammasomes
Inflammasomes are cytosolic protein complexes that play a central role in the innate immune system’s ability to detect and respond to danger. Upon sensing pathogen-associated or damage-associated signals, specific sensor proteins, such as NLRP3, AIM2, and NLRP1, undergo conformational changes that drive the assembly of a multiprotein signaling platform. This event culminates in the recruitment and activation of caspase-1, which processes the pro-inflammatory cytokines IL-1β and IL-18 into their mature, bioactive forms. Concurrently, caspase-1 cleaves gasdermin D (GSDMD), liberating its N-terminal fragment to form pores in the plasma membrane, ultimately inducing pyroptosis, a highly inflammatory form of programmed cell death that facilitates the release of cytokines and danger signals into the extracellular space (Fig. 1) [69].
Inflammasome activation is subject to tight regulatory control, typically requiring a two-step process: an initial priming signal, which induces the expression of inflammasome components and cytokine precursors, followed by a second trigger, often involving ionic imbalance, mitochondrial dysfunction, or cytosolic nucleic acids, that activates the inflammasome complex. This dual-signal requirement ensures that inflammasome responses are engaged only when truly needed. Nevertheless, chronic or dysregulated activation, arising from genetic mutations, metabolic stress, or persistent immune stimulation, can result in sustained inflammation and contribute to disease pathology [70].
Among inflammasome types, NLRP3 is the most broadly responsive, capable of integrating a wide variety of sterile and infectious stressors. In contrast, AIM2 responds specifically to cytosolic double-stranded DNA and assembles rapidly without requiring prior transcriptional priming.
While transient inflammasome activation is essential for host defense and tissue repair, persistent signaling can drive pathological inflammation. Dysregulated inflammasome pathways are associated with a wide range of diseases, from monogenic syndromes such as familial Mediterranean fever and cryopyrin-associated periodic syndromes to multifactorial conditions including atherosclerosis, neurodegenerative diseases, metabolic disorders, and inflammatory bowel disease [70]. The continuous production of IL-1β and IL-18, together with pyroptotic cell death, can destabilize tissue homeostasis, enhance immune cell infiltration, and impair normal cellular functions, ultimately leading to chronic tissue injury.
Given their central role in regulating inflammation and cell fate, inflammasomes, particularly NLRP3 and AIM2, have garnered growing attention as potential drivers of hematologic malignancies, including AML, where inflammatory signals are now recognized as critical factors in disease initiation, maintenance, and progression.

Inflammasomes in AML
Inflammasomes, particularly NLRP3, are emerging as key contributors to the pathophysiology of AML, operating both within leukemic cells and in the BM microenvironment. Several studies have reported aberrant activation of the NLRP3 inflammasome in AML. Transcriptomic analyses revealed that NLRP3, IL-1β, NF-κB, and IL-1R are significantly upregulated in AML samples compared with healthy controls, whereas the expression of ASC, caspase-1, and IL-18 remains largely unchanged [71]. Consistent with these findings, increased circulating levels of the downstream effector IL-1β have been detected in AML patients. Functionally, NLRP3 activation promotes leukemic cell proliferation and confers resistance to apoptosis, partly through upregulation of the oncogenic proteins Bcl-2 and c-Myc following LPS priming of inflammasome activation. Moreover, NLRP3 activation diminishes the cytotoxic efficacy of chemotherapeutic agents such as adriamycin and daunorubicin, suggesting that inflammasome signaling contributes to both disease progression and therapy resistance in AML [71].
Caspase-1 activation and IL-1β production are especially pronounced in patients harboring KRAS mutations [72]. In the same study, the role of the NLRP3 inflammasome in AML was validated in vivo using a hematopoietic-specific KrasG12D mouse model, where NLRP3 deficiency reversed both myeloproliferation and associated cytopenias. Moreover, cytarabine and other widely used chemotherapeutic agents, can activate NLRP3 inflammasome and induce IL-1β release [73]. These observations suggest that inflammasome signaling is not merely a consequence of leukemic transformation but may actively drive disease progression and influence therapy response. Indeed, elevated IL-1β levels have been associated with reduced overall survival and poor response to chemotherapy, highlighting the prognostic and therapeutic relevance of inflammasome activity in AML [71, 74].
Mechanistically, inflammasome signaling promotes leukemogenesis through several pathways. IL-1β, a key downstream effector, acts in both autocrine and paracrine manners to promote AML blast proliferation and survival via NF-κB and MAPK activation [71, 74]. It also disrupts normal hematopoiesis by impairing the differentiation, expansion, and function of healthy HSPCs, thereby favoring a selective advantage for leukemic clones [19]. This effect creates a proinflammatory and dysfunctional BM environment in which malignant cells thrive at the expense of normal hematopoietic output. Additionally, persistent IL-1β and IL-18 release alters the immune landscape promoting the expansion of immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs), regulatory T cells, and alternatively activated macrophages (M2-like), all of which hamper anti-leukemic immunity [75, 76]. Inflammasome activation in the BM stromal and accessory cells may further exacerbate this inflammatory niche and impairs immune-stromal interactions essential for normal hematopoiesis [77–79].
Beyond cytokine signaling, inflammasome-mediated pyroptosis via GSDMD has also been implicated in AML. This form of lytic cell death likely fuels a self-sustaining inflammatory loop that promotes leukemic cell fitness, damages the BM niche, and contributes to immune suppression. Elevated levels of pyroptosis-related transcripts, including GSDMD, have been associated with poor overall survival in AML patients, underscoring their potential prognostic value [80, 81].
A recent study has also uncovered a link between NLRP3 inflammasome signaling and the PERK/eIF2α axis, a key regulator of the unfolded protein response. Pharmacological inhibition of NLRP3 dampened PERK/eIF2α activation, resulting in decreased leukemic cell proliferation and survival [82]. These findings suggest that inflammasome activity in AML extends beyond IL-1 signaling and may intersect with cellular stress response pathways to sustain disease progression.
Another layer of complexity is that inflammasome activity varies by AML subtype and disease stage. Caspase-1 expression is particularly elevated in monocytic AML subtypes, where myeloid differentiation promotes upregulation of inflammasome components [83]. Newly diagnosed AML patients also exhibit increased expression of NLRP3 inflammasome components in BM mononuclear cells, with NLRP3 levels positively correlating with ASC and IL-1β [84].
While NLRP3 is the most studied inflammasome in AML, AIM2 has recently emerged as a key player, particularly in FLT3-mutant cases. Elevated AIM2 expression in BM samples correlates with poor prognosis and reduced T-cell infiltration, suggesting a role in immune evasion and leukemic stem cell maintenance [85]. In AML cell lines (HL-60, THP-1, KG-1a) AIM2 knockdown reduces proliferation, induces apoptosis, and downregulates cell cycle regulators, such as cyclin D1 and CDK2 following treatment with all-trans retinoic acid combined with autophagy inhibition, which leads to cytosolic DNA accumulation [86]. Mechanistically, cytosolic DNA is sensed by AIM2, which activates the canonical inflammasome pathway and caspase-1. This cascade results in stabilization of the cell cycle inhibitor CDKN1A p21 by preventing its proteasomal degradation, thereby enforcing terminal differentiation and irreversible growth arrest. Collectively, these findings suggest a dual role for AIM2 in AML: under steady-state conditions, it promotes leukemic proliferation and survival; upon therapeutic induction of cytosolic DNA stress (e.g., via autophagy inhibition), it supports differentiation and halts cell growth. This context-dependent behavior positions AIM2 as a potential therapeutic target, particularly in combination with agents that modulate intracellular stress responses.
Inflammasome signaling may also contribute to therapy resistance. Treatment-related stressors, including chemotherapy and radiation, can activate inflammasomes, protecting leukemic stem cells from cytotoxic damage and favoring disease relapse [71, 87, 88]. Radiation exposure has been shown to trigger NLRP3 activation, leading to pyroptotic cell death, persistent inflammation, and tissue fibrosis—mechanisms that may promote leukemic cell survival within a pro-inflammatory microenvironment [87]. Similarly, chemotherapeutic agents such as doxorubicin can activate both AIM2 and NLRP3 inflammasomes in macrophages and neutrophils, inducing pyroptosis and NETosis and driving the release of IL-1β and IL-18 relapse [71, 88]. These processes not only mediate systemic inflammatory toxicity, such as chemotherapy-induced bone loss, but may also establish an inflammatory milieu that protects leukemic cells from cytotoxic injury. In AML, NLRP3 activation has been shown to enhance proliferation and drug resistance, effects that can be reversed by caspase-1 or NF-κB inhibition [71, 89]. Collectively, these findings indicate that inflammasome-driven inflammation represents both a driver of therapy resistance and a promising target for therapeutic intervention.
Inflammasome-related biomarkers could help stratify patients based on inflammatory status and predict response to therapy [90]. Transcriptomic analyses revealed that poor responders to FLT3 inhibitors or venetoclax (BCL2 inhibitor) display enrichment of inflammasome and autophagy gene signatures [91]. Moreover, elevated AIM2 expression has been linked to increased sensitivity to certain tyrosine kinase inhibitors (e.g., nilotinib, dasatinib, midostaurin) but resistance to venetoclax, highlighting its potential relevance in therapy stratification [92]. Persistent activation of the AIM2 inflammasome by cytosolic double-stranded DNA—released from damaged cells following radio- or chemotherapy—may sustain IL-1-driven inflammation and promote leukemic stem cell survival. This chronic pro-inflammatory signaling fosters adaptive stress responses, metabolic and transcriptional plasticity, and ultimately contributes to resistance and relapse in AML.
In summary, inflammasomes, particularly NLRP3 and AIM2, play multifaceted roles in AML pathogenesis, progression, immune evasion, and treatment resistance. Their activation shapes the leukemic niche, impairs normal hematopoiesis, and alters immune surveillance. Given their dual roles and context-dependent effects, targeting inflammasome pathways may offer novel therapeutic opportunities in AML. Further studies are warranted to validate biomarkers of inflammasome activity and assess the impact of inflammasome inhibition on immune competence in AML patients.

Strategies for inflammasome inhibition in AML
Given the pathological role of inflammasome signaling in AML and other myeloid malignancies, such as MDS and myeloproliferative neoplasms (MPN), key components of this pathway are under active investigation as therapeutic targets. In preclinical AML models, both genetic and pharmacologic inhibition of NLRP3 or IL-1β signaling has been shown to reduced leukemic cell growth and improved hematopoietic recovery [71].
Among direct inhibitors, the small molecule MCC950, a selective NLRP3 inhibitor, has demonstrated significant efficacy in preclinical models of inflammasome-driven diseases, including AML [71, 82, 93]. However, its clinical development was halted due to hepatotoxicity, promptly the search for safer derivatives with comparable specificity. Several other indirect NLRP3 inhibitors have shown promise in preclinical settings [94]. These include 3,4-methylenedioxy-β-nitrostyrene (MNS) and CY-09, a CFTR inhibitor analog that blocks ATP binding to NLRP3 without affecting other NOD-like receptors. Additionally, compounds like tranilast and OLT1177 have demonstrated efficacy in animal models and ex vivo studies, and are being explored for their potential as therapeutic agents in NLRP3-driven malignancies [95, 96]. The Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib has been shown to interact directly with ASC and NLRP3, preventing the formation of the inflammasome complex and caspase-1 activation [97]. Ibrutinib, in combination of with lenalidomide and 5’-azacytidine (AZA), is currently being assessed in early-phase clinical trials for high-risk MDS (NCT03359460 and NCT02553941) [98, 99]. Unfortunately, although the preclinical results looked promising, ibrutinib alone, or in combination with cytarabine or AZA, in AML patients unfit for standard therapy or with relapsed/refractory disease did not show clinically relevant anti-leukemia activity [100]. Although their use in myeloid malignancies like AML and MDS has not yet been explored, compounds that target caspase-1 activity or GSDMD may offer a novel approach to correcting inflammasome-driven hematopoietic imbalance. The small-molecule inhibitor Val-boroPro (also known as PT100 or talabostat) has been shown to induce pyroptosis in AML cell lines and primary patient samples, suggesting that pharmacologic activation of pyroptotic pathways may represent a viable strategy to eliminate leukemic cells. By targeting dipeptidyl peptidases, Val-boroPro triggers caspase-1 activation and GSDMD cleavage, leading to inflammatory cell death. These findings point to the therapeutic potential of harnessing pyroptosis to overcome resistance and eradicate leukemic blasts, particularly in subtypes that evade apoptosis-based treatments [101].

Conclusions and perspectives
Over the past decades, our understanding of the complex interplay between inflammation and AML has expanded substantially. Among the many inflammatory mediators implicated in leukemogenesis, IL-1 signaling and inflammasome activation have emerged as central drivers of disease progression, immune evasion, and therapeutic resistance. A growing body of evidence indicates that IL-1β not only sustains leukemic blast proliferation but also remodels the BM microenvironment to favor malignant expansion at the expense of normal hematopoiesis. Likewise, aberrant activation of inflammasome components—particularly NLRP3 and AIM2—further amplifies inflammation and disrupts immune surveillance, reinforcing a self-perpetuating pro-leukemic niche.
Despite promising preclinical data and increasing interest in targeting these inflammatory pathways, several critical challenges remain. The precise contribution of IL-1 and inflammasome signaling across AML subtypes and disease stages is not fully understood, and their functional roles in leukemic stem cells versus the stromal or immune compartments require further investigation. Moreover, while clinical trials of IL-1 blockers and inflammasome inhibitors are underway in AML and other myeloid-related malignancies (i.e. myelodysplastic neoplasms), it remains unclear which patient subsets would benefit most from these interventions.
Future efforts should focus on integrating inflammatory biomarkers into risk stratification tools, identifying combination strategies that potentiate the efficacy of anti-inflammatory agents, and carefully evaluating their impact on anti-leukemic immunity. Given the context-dependent roles of IL-1 and inflammasomes in hematologic malignancies, a deeper mechanistic understanding will be crucial to unlock their full therapeutic potential.