PPARδ: An underappreciated tumor accelerator in pancreatic ductal adenocarcinoma.

1.
Introduction
Pancreatic cancer, predominantly pancreatic ductal adenocarcinoma (PDAC), is one of the most aggressive malignancies and has a dismal prognosis, with a 5-year survival rate of approximately 13% [1]. PDAC is currently the third-leading cause of cancer-related deaths in the United States and is projected to rise to the second place by 2030 [2, 3]. The poor clinical outcomes and high mortality rates of PDAC are largely attributable to its late-stage diagnosis, early metastasis, and intrinsic biological features, including pronounced tumor heterogeneity, extensive desmoplastic stroma, and a highly immunosuppressive tumor microenvironment (iTME), which together confer substantial resistance to chemotherapy, targeted therapy, and immunotherapy [4, 5]. PDAC typically develops from normal glandular epithelium through a stepwise progression of precursor lesions, most notably pancreatic intraepithelial neoplasia (PanIN), which frequently carries oncogenic KRAS mutations that have been recognized as a driver of pancreatic tumorigenesis [6].
PanIN lesions (PanINs) are frequently observed in adult human pancreases. Autopsy studies have demonstrated a high prevalence, with PanINs detected in approximately 86% of 154 cases (90% of which were in individuals aged ≥ 40 years) [7] and in 78% of 173 cases with a mean age of 80.5 years (range, 26–103 years), where PanIN-1, PanIN-2, and PanIN-3 accounted for 77%, 28%, and 4%, respectively [8]. Although PanINs are an almost universal presence in aging pancreata [9], fortunately only a small proportion of these precursor lesions ultimately progress to invasive PDAC [10–13]. These findings underscore the urgent need to identify risk factors that promote PanIN progression to invasive PDAC and to elucidate the poorly understood molecular mechanisms underlying this transition, thereby enabling the development of effective therapeutic interventions.
Peroxisome proliferator-activated receptor delta (PPARδ) is a ligand-activated transcription factor belonging to the nuclear receptor superfamily [14]. PPARδ is broadly expressed across tissues, with levels varying by cell type and pathological context [15]. Functioning as obligate heterodimers with other coactivator factors such as retinoid X receptors upon ligand binding, PPARδ regulates expression of its downstream genes, playing critical roles in lipid metabolism, cell differentiation, tissue development, cellular homeostasis, inflammation, and tumorigenesis [15–19]. In normal tissues, PPARδ promotes fatty acid catabolism and energy expenditure in adipose tissue, muscle, and liver, while suppressing macrophage-mediated inflammation [20]. Together, these activities make PPARδ a multifaceted therapeutic target for metabolic syndrome, with the potential to control weight gain, enhance physical endurance, improve insulin sensitivity, and ameliorate atherosclerosis [20]. Although selective PPARδ agonists such as GW501516 showed significant reductions in triglycerides and increases in high-density lipoprotein cholesterol and insulin sensitivity in early-phase clinical trials [21–24], GW501516 was halted in development due to its potential to promote tumorigenesis in preclinical models [25–28]. These findings underscore the need for a deeper understanding of PPARδ’s biological functions, particularly in cancers.
PPARδ is upregulated in a range of human malignancies, including pancreatic [26, 29], colorectal [19, 30], lung [31], breast [32], and gastric cancers [33, 34], indicating its potential role in promoting tumorigenesis across diverse tissue types. Although the functions of PPARδ have been initially studied in several other cancer types [19, 25, 28, 31–37], recent work has highlighted its important role in pancreatic tumorigenesis, where it integrates oncogenic, metabolic, and immune-regulatory signals to collectively accelerate disease progression [26, 29, 38–40]. In this brief review, we summarized the roles and mechanistic actions of PPARδ in PDAC progression and discussed its therapeutic potential in PDAC. While the field remains in its early stages and further studies are required, this review provides a timely perspective for the audience.

2.
PPARδ in PDAC tumorigenesis and progression
2.1.
Interaction of PPARδ and oncogenic KRAS activations.
KRAS mutations represent a predominant genetic alteration in PDAC, occurring in approximately 93% of patients, with the KRASG12D (KRASmu) variant present in around 45% [41, 42]. While KRAS functions as a critical proto-oncogene, low-grade PanIN lesions harboring KRAS mutations are frequently observed in otherwise adults without clinical manifestations. Similarly, preclinical models require additional cofactors to drive KRASmu-initiated neoplastic transformation [43].
PPARδ rapidly accelerates KRASmu-initiated pancreatic tumorigenesis in mice [26]. In genetically engineered KRASmu mice, activation of PPARδ by its ligands, such as a high-fat diet or the highly selective synthetic agonist GW501516, markedly increases pancreatic neoplastic lesions and accelerated progression from PanIN to PDAC [26]. Tumorigenic effect is accelerated in KRASmu mice with transgenic pancreatic PPARδ overexpression, whereas tumorigenic effect of KRASmu is drastically attenuated in mice with pancreatic PPARδ deletion [26]. Together, these complementary findings demonstrate that PPARδ plays a critical role in promoting KRASmu-initiated pancreatic tumorigenesis.
Previous studies have reported that PPARδ is upregulated in the late stages of PDAC [29, 39]. Recent work demonstrates that PPARδ is also elevated in human and mouse PanINs, and this increase is positively associated with KRASmu activity during tumor progression. In KRASmu mice, increased KRASmu activity is associated with PPARδ upregulation in PanINs and PDAC. In vitro and in vivo experiments using doxycycline-inducible KRASmu mouse PDAC cell lines show that KRASmu activation significantly increases PPARδ mRNA and protein levels, whereas inhibition of KRASmu signaling with the mitogen-activated protein kinase inhibitor PD0325901 significantly reduces PPARδ expression at both transcript and protein levels [26].
Furthermore, ligand-mediated PPARδ activation induces pancreatic epithelial cells to secrete C-C motif chemokine ligand 2 (CCL2), recruiting immunosuppressive tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) into the pancreas via the CCL2/C-C motif chemokine receptor 2 (CCR2) axis [26]. IL6/STAT3 signaling is essential for the progression of KRASmu pancreatic tumors [44, 45], and PPARδ activation by GW501516 or a high-fat diet markedly increases IL6 and p-STAT3 (Tyr705) levels in KRASmu mice, regardless of pancreatic PPARδ overexpression [26].
A threshold model of KRASmu activity explains why PanINs rarely progress to invasive PDAC without additional critical factors such as inflammation in adulthood [43]. In this study [26], the interplay among PPARδ, KRASmu, and inflammatory signals creates a positive feedback loop that amplifies and sustains oncogenic KRAS activity at levels sufficient for malignant transformation. This mechanism likely underlies PPARδ’s role in accelerating both the initiation and progression of KRASmu pancreatic tumorigenesis and provides a strong rationale for targeting PPARδ therapeutically in PDAC (Figure 1).

2.2.
PPARδ and metabolic reprogramming in PDAC invasiveness and metastases
Metabolic reprogramming is a hallmark of cancer, enabling tumor cells to meet the increased demands for biomass, energy, and macromolecules required for uncontrolled proliferation [46]. In PDAC, over 90% of patients harbor activating KRAS mutations [41] and additional genetic alterations, such as mutations, deletions, or amplifications in genes including cyclin dependent kinase inhibitor 2A (CDKN2A), tumor protein p53 (TP53), SMAD family member 4 (SMAD4), phosphatase and tensin homolog (PTEN), and MYC proto-oncogene, bHLH transcription factor (MYC) remodel PDAC metabolism in distinct ways [47, 48]. These alterations profoundly impact key metabolic pathways, including glycolysis, glutamine utilization, micropinocytosis, and autophagy [49–51]. PDAC is also characterized by pronounced desmoplasia and hypoxia, driven by abundant cancer-associated fibroblasts (CAFs) that deposit extracellular matrix to form a dense fibrotic stroma [52, 53]. This stromal compartment exerts dual functions: it can restrict tumor expansion while simultaneously compressing vasculature, generating a hypoxic, nutrient-poor microenvironment [54, 55]. To survive and proliferate in these hostile conditions, PDAC cells dynamically reprogram their metabolism in response to fluctuations in nutrient and oxygen availability.
Recent studies show that metabolic reprogramming in PDAC involves a complex coordination of mitochondrial and glycolytic activity, modulated by PPARδ in conjunction of the MYC/PPARγ coactivator 1 alpha (PGC1A) balance and epithelial-to-mesenchymal transition (EMT) induction in response to tumor microenvironmental cues [38]. In the context, partial mitochondrial inhibition via mitochondrial long-term-chain fatty acid transporter blocker etomoxir or M2-like TAMs-derived conditioned medium, mimicking nutrient deprivation and tumor microenvironmental cues commonly present in PDAC, alters the lipidome and activates PPARδ, rewiring cellular metabolisms and enhancing invasiveness and metastases [38]. This metabolic reprogramming is associated with an increased ratio of MYC to PGC1A expression, which shifts energy production toward glycolysis while decreasing mitochondrial activity such as oxidative phosphorylation (OXPHOS). Genetic or pharmacologic inhibition of PPARδ prevents this metabolic shift, suppresses invasion in vitro, and reduces metastasis in vivo [38].
Single-cell transcriptomic analyses reveal that PPARδ is selectively elevated in PDAC cell subsets transitioning from epithelial to mesenchymal states, a pattern consistently validated in primary PDAC cultures [38]. PPARδ integrates nutrient stress and microenvironmental signals to promote EMT and invasiveness, upregulating expression of EMT-associated genes such as vimentin (VIM) and zinc finger E-box binding homeobox 1 (ZEB1), while coordinating mitochondrial and glycolytic remodeling. These metabolic alterations are tightly linked to EMT induction, enabling cancer cells to adapt to hostile microenvironments and facilitating metastatic dissemination [38]. In other malignancies such as colorectal cancer cells, PPARδ directly upregulates a network of pro-metastatic genes, including VIM, gap junction protein alpha 1 (GJA1), secreted protein acidic and rich in cysteine (SPARC), stanniocalcin 1 (STC1) and synuclein gamma (SNCG) thus drastically promoting EMT, migration, and invasion [19]. Collectively, these findings establish PPARδ as a key driver of metabolic reprogramming that promotes a pro-metastatic phenotype in PDAC, highlighting PPARδ inhibition as a potential therapeutic approach to suppress PDAC progression (Figure 2).
Ferroptosis is a type of controlled cell death caused by the iron-dependent buildup of lipid peroxides on the cell membrane. Emerging evidence suggests that PPARδ plays a function in lipid and redox metabolism, influencing ferroptosis through multiple methods. PPARδ acts as a novel transcriptional regulator of long-chain acyl-CoA synthetase 4 (ACSL4), a key pro-ferroptotic enzyme, driving upregulation of ACSL4 expression, particularly in the liver and testis under high-carbohydrate high-fat diet conditions [56]. In contrast, PPARδ activation has also been reported to increase hepatic expression of ACSL3, an enzyme associated with monounsaturated fatty acid synthesis and ferroptosis resistance [57]. These findings suggest a potential link between PPARδ signaling and ferroptotic vulnerability; direct experimental evidence remains limited and warrants further validation. Another study indicates that GW501516-mediated PPARδ activation suppresses ferroptosis by upregulating catalase, which stabilizes peroxisomes and lysosomes to limit iron accumulation and lipid peroxidation [58]. Moreover, emerging evidence suggests that in the context of KRAS mutations, suppression of ferroptosis enables PDAC cells to withstand metabolic stress, contributing to chemoresistance and poor clinical outcomes; consequently, induction of ferroptosis may represent a promising therapeutic strategy in PDAC [59].

2.3.
PPARδ and immunosuppression in PDAC
A defining histopathological hallmark of PDAC is the extensive desmoplastic reaction seen in both primary and metastatic lesions [60]. Tumor-secreted cytokines and growth factors activate quiescent pancreatic stellate cells (PSCs) into myofibroblast-like cells that deposit abundant extracellular matrix proteins, generating a dense fibrotic stroma. This desmoplastic response compresses blood vessels, impairs vascular perfusion, limits drug delivery, and restricts immune-cell infiltration, thereby leading to therapeutic resistance and establishing an iTME [54, 61, 62]. Cancer cells exploit these stromal alterations to create a niche that promotes tumor growth, invasion, and immune evasion. PDAC progression is also reinforced by the accumulation of immunosuppressive cell populations including MDSCs, TAMs, and regulatory T cells (Tregs), which together sustain the highly iTME [63].
PPARδ has emerged as a potential component of the angiogenic gene network governed by the APC/β-catenin/PPARδ axis. APC, a negative regulator of β-catenin, acts as an anti-angiogenic gene, whereas PPARδ, together with β-catenin and its downstream targets such as Cyclin D1 and MYC, functions as a pro-angiogenic factor. Immunohistochemical analyses show that PPARδ expression is markedly increased in chronic pancreatitis, primary, and metastatic PDAC lesions compared with surrounding normal pancreatic tissue [29, 38]. The upregulation is especially prominent in the tumor vasculature and stromal compartments, including fibroblasts, and is positively associated with the development of a pro-angiogenic microenvironment [29] but negatively correlated with patient disease-free survivals [38]. In other malignancies, PPARδ is upregulated in human squamous cell carcinoma, where its expression positively correlates with tumor vessel density [64]. Consistently, across multiple preclinical tumor models [65], endothelial-specific overexpression or pharmacologic activation of PPARδ increases microvascular density, accelerates tumor growth, and promotes distant metastasis [66]. In contrast, downregulation of PPARδ in cancer cells suppresses angiogenesis and metastatic progression [19], while tumor angiogenesis and growth are markedly inhibited in PPARδ knockout mice [67].
Ligand-mediated PPARδ activation in KRASmu pancreatic epithelial cells induces the secretion of chemokine CCL2, which in turn recruits immunosuppressive macrophages such as MDSCs and M2-TAMs via the CCL2/CCR2 axis [26]. This immune remodeling accelerates the progression from PanIN to PDAC [26]. This PPARδ activation also upregulates inflammatory pathways, notably IL6/STAT3 signaling pathway [26]. Pharmacological inhibition of CCR2 effectively reduces the infiltration of MDSCs and TAMs and suppresses PDAC progression [26].
Glutamic-oxaloacetic transaminase 2 (GOT2), known as mitochondrial aspartate aminotransferase, is a key metabolic enzyme localized in the mitochondria. GOT2 enhances PPARδ transcriptional activity by directly binding fatty acids, including arachidonic acid [40]. GOT2 deficiency in PDAC cells markedly decreases pancreatic xenograft tumor weight in vivo and increases infiltration of CD4⁺ and CD8⁺ T cells, while decreasing immunosuppressive TAMs. Conversely, pharmacological activation of PPARδ by GW501516 reverses these effects, promoting tumor growth and immunosuppression in preclinical models [40]. Mechanistically, GOT2 facilitates PPARδ activation via binding its fatty acid ligands and subsequently upregulates the expression of PPARδ downstream targets such as COX2 (encoded by PTGS2), M-CSF (encoded by CSF1), Pancreatitis-associated protein (PAP, encoded by REG3G) which has been reported to suppress anti-tumor immunity [68], highlighting the GOT2–PPARδ/COX2 signaling as a key regulator linking metabolism to immune suppression in PDAC progression [40]. Collectively, these findings underscore the critical role of PPARδ in shaping tumor immunosuppressive landscape and suppressing antitumor immunity in PDAC, highlighting its potential as a therapeutic target for PDAC (Figure 3).

3.
PPARδ as a potential therapeutic target in cancers
3.1.
Overview of PPARδ antagonists and inverse agonists
Accumulating evidence that PPARδ promotes tumorigenesis and progression, including in PDAC, has spurred the development of antagonists and inverse agonists as potential cancer therapeutics. Antagonists are small-molecule compounds that bind the receptor’s ligand-binding domain, preventing activation by endogenous ligands or synthetic agonists; some, particularly irreversible antagonists, stabilize an inactive receptor conformation [69]. Inverse agonists not only block agonist-induced receptor activation but also actively recruit corepressor complexes to repress basal transcription of PPARδ transcriptional activity [69]. Both classes of compounds aim to inhibit oncogenic programs regulated by PPARδ, ultimately suppressing tumor growth. Key example compounds are summarized below.

3.2
PPARδ antagonists

GSK0660 (Selective/Competitive antagonist):
The earliest known highly selective PPARδ antagonist, GSK0660, was discovered in 2008 [70, 71]. The thiophene-based chemical binds to the PPARδ ligand-binding domain (LBD) with great affinity but has minimal activation effects on PPARα and PPARγ. GSK0660 is mostly a tool chemical in research. In animal models, topical treatment reduces UV-induced PPARδ activation and skin tumor growth [72]. GSK0660 at 100 nM reduces carnitine palmitoyltransferase 1A (CPT1a) expression in skeletal muscle cells to 50% of baseline levels, while having no significant effect on pyruvate dehydrogenase kinase Isozyme 4 (PDK4) expression (another PPARβ/δ target gene) [70]. Although limited bioavailability hinders clinical translation, GSK0660 inhibits PPARδ activity and downregulates oncogenic signaling pathways like Src, Lin28, EGFR/Erk1/2, and TGF-β1, providing pharmacological evidence for PPARδ’s role in tumorigenesis [72].

SR13904 (Competitive antagonist):
SR13904 is a small-molecule antagonist of PPARδ generated through structural modification of the highly selective agonist GW501516 [73]. SR13904 binds to the LBD and competitively inhibits agonist-induced PPARδ transcriptional activity. Its IC50 is 2.4 μM, while its IC50 for PPARγ is about 9.0 μM, showing that it is very selective for one subtype. At the functional level, SR13904 shows significant anti-proliferative activity in a variety of cancer cell lines, such as lung cancer (A549), breast cancer (MCF-7) and liver cancer (Huh7), and its effect was directly related to the inhibition of PPARδ signaling pathway [73, 74].

GSK3787 (Selective and irreversible PPARδ antagonist):
GSK3787 is a highly selective, irreversible PPARδ antagonist developed by GlaxoSmithKline in 2010. GSK3787 is a covalent PPARδ antagonist that inhibits PPARδ transcriptional activity in both in vitro and in vivo environments by targeting the Cys249 residue within the LBD. This covalent interaction confers high affinity and selectivity for PPARδ (pIC50 ≈ 6.7), with substantially weaker activity against PPARα and PPARγ (pIC50 < 5) [75]. GSK3787 suppresses colonic tumorigenesis by downregulating Wnt/β-catenin targets, including c-Myc and Cyclin D1, thereby reducing proliferation and invasion [27, 75, 76]. In addition, GSK3787 inhibits gastric tumorigenesis by modulating CCL20/CCR6 axis, enhancing anti-cancer immunity [77].

PT-S58 (Selective/Competitive antagonist):
PT-S58 is a structurally optimized PPARδ inhibitor derived from GSK0660 and is distinguished as a pure antagonist rather than an inverse agonist. It blocks both agonist- and inverse agonist-mediated PPARδ activity without inducing receptor conformational changes or recruiting corepressors [78]. PT-S58 selectively inhibits PPARδ agonist–driven reporter activity while sparing PPARα and PPARγ and shows minimal effects on basal target gene expression [78]. Using PT-S58 as a tool compound, Levi et al. demonstrates that inhibition of PPARδ suppresses proliferation of fatty acid binding protein 5 (FABP5)-high cancer cells and enhances saturated fatty acid–induced apoptosis via retinoic acid receptor (RAR) activation [79].

3.3
PPARδ inverse agonists

ST247 (Inverse agonist):
ST247 is a high-affinity ligand specific to PPARδ, characterized as an inverse agonist with distinct pharmacological properties. ST247, a derivative of GSK0660, was acquired via structural optimization. Competitive binding assays indicate an IC50 value of 93 nM for ST247 at PPARδ, surpassing GSK0660 (IC50=310 nM), while exhibiting subtype selectivity and minimal impact on PPARα and PPARγ [78]. ST247 functions as an inverse agonist, facilitating the interaction between PPARδ and core repressors, such as silencing mediator of retinoid and thyroid hormone receptors (SMRT), thereby enhancing the recruitment of core repressors [78]. In breast cancer cells, ST247 modulates the PPARδ-angiopoietin-like 4 (ANGPTL4) axis through inverse agonism, thereby effectively inhibiting invasive behavior [80].

DG172 (Inverse agonist):
DG172 is an orally bioavailable PPARδ selective inverse agonist initially identified through NCI compound library screening and subsequently structurally optimized. This compound exhibits high affinity and significant subtype selectivity for PPARδ, effectively inhibiting basal transcriptional activity in cells and downregulating expression of the classic target gene ANGPTL4 [81]. Mechanistically, DG172 inhibits transcription initiation by forming a non-canonical inhibitory complex that blocks RNA polymerase II recruitment to the ANGPTL4 promoter, independent of HDACs or traditional core repressors. Functional studies demonstrate that DG172 significantly suppresses TGF-β or serum-induced invasion in MB-231 breast cancer cells. Notably, DG172 exhibits favorable pharmacokinetic characteristics in mice, supporting its use as an effective tool compound for in vivo studies [80, 81].

4.
PPARδ as a potential therapeutic target in PDAC
4.1.
PPARδ and KRAS inhibition and resistance in PDAC
KRAS mutations occur in over 90% of PDAC and drive tumor initiation, metabolic rewiring, and immune evasion [82–84]. The development of KRASG12D inhibitors, such as MRTX1133, RMC-9805, also known as zoldonrasib, KRASG12C inhibitors (e.g., adagrasib, sotorasib), and Pan-Ras inhibitors (e.g., RMC-6236) represents a breakthrough in PDAC targeted therapy, yet resistance emerges rapidly [85]. The mechanisms of this resistance are diverse. Genetic factors include secondary KRAS mutations, PIK3CA mutations, and amplification of oncogenes such as KRASG12C, MYC, MET, EGFR, and CDK6. Non-genetic contributors involve processes such as EMT and activation of the mTOR pathway. In addition, shifts in tumor cell states contribute, as mesenchymal-like and basal-like phenotypes exhibit reduced sensitivity to KRAS inhibition. Transcriptional reprogramming toward YAP1-driven or EMT-like programs further enables tumor cells to escape therapeutic pressure [86].
Importantly, resistance is not only tumor-cell intrinsic but is also shaped by the TME.Remodeling of TME, particularly through the activity of lysine acetyltransferase 2B in CAFs and TAMs, promotes resistance by secreting growth factors and cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF) [52, 87]. In KPC mouse models, resistant tumors show amplification of genes including YAP1, KRAS, MYC, and CDK6, accompanied by adaptive changes in the microenvironment such as reduced immune cell infiltration and upregulation of immunosuppressive mediators [86]. CAFs play a direct role by releasing factors like neuregulin-1 (NRG1), which engage erb-b2 receptor tyrosine kinase 2/3 (ERBB2/ERBB3) receptors on PDAC cells to restore PI3K/AKT signaling and sustain tumor growth despite KRAS suppression [88]. TAMs also contribute: KRAS blockade in PDAC can induce expression of chemokines (CCL2/CCL7) that recruit macrophages, which secrete TGF-β and activate SMAD4-dependent survival pathways in cancer cells [89]. Through such paracrine mechanisms, stromal cells reinstate mitogen-activated kinase-like protein (MAPK) and AKT signaling in the presence of KRAS inhibitors. Mouse models show enrichment of stem-like cell populations and persistence of an immunosuppressive niche after KRAS inhibition, further limiting durable responses [86]. This TME-driven resilience limits the depth and duration of KRAS inhibitor responses.
Metabolic dysregulation is a major driver of resistance in PDAC. When KRAS signaling is blocked, tumor cells adapt by shifting fuel use and activating survival pathways. In PDAC, cells that survive KRAS ablation become more reliant on mitochondrial oxidative phosphorylation and autophagy while reducing their dependence on glycolysis [90]. Lipid metabolic rewiring is another facet of resistance. PDAC cells can increase fatty acid oxidation and scavenge extracellular lipids to fuel ATP production and membrane synthesis when glycolytic pathways are restricted. High lipid availability has been linked to tumor progression and metastasis, as cancer cells exploit lipids for energy and to modulate immune cells in the TME, ultimately promoting therapy resistance and relapse [91, 92]. However, Parejo-Alonso et al. recently reported that nutrient starvation and microenvironmental cues activate PPARδ, promoting PDAC invasiveness and metastasis through metabolic rewiring characterized by increased glycolysis and reduced OXPHOS [38]. Additionally, alterations in metabolic regulators like PPARδ illustrate how metabolic plasticity confers drug resistance. In one study of sorafenib-resistant liver cancer, upregulation of PPARδ reprogrammed glutamine metabolism, boosting the tricarboxylic acid cycle and nicotinamide adenine dinucleotide phosphate (NADPH) production to maintain redox balance [93].
Collectively, these findings highlight that both the TME and metabolic plasticity, including PPARδ-mediated iTME and metabolic rewiring (Figure 1–3), play central roles in resistance to KRAS inhibition in PDAC.

4.2.
Therapeutic potential of co-targeting PPARδ and oncogenic KRAS
PPARδ is upregulated in PanINs and PDAC and, when activated by ligands such as high-fat diet components or synthetic agonists (e.g., GW501516), accelerates KRASmu-driven tumorigenesis and progression via forming a positive feedback loop between PPARδ and oncogenic KRAS [26] (Figure 1). Accordingly, targeting PPARδ either alone or in combination with oncogenic KRAS inhibition may disrupt this pathogenic signaling circuit, induce tumor regression, and delay the emergence of therapeutic resistance. Indeed, recent studies demonstrate that pharmacologic inhibition of PPARδ using antagonists (GSK0660, GSK3787) or the inverse agonist DG172 effectively suppresses PDAC invasiveness in vitro and significantly reduces metastatic dissemination in spontaneous metastasis models following orthotopic implantation of metastatic PDAC cells [38]. Available pharmacologic agents including KRASG12D inhibitors such as MRTX1133 [85] and RMC-9805 [94], together with PPARδ antagonists and inverse agonists (e.g., GSK3787, DG172), provide an unique opportunity to rigorously evaluate this dual-targeting strategy in preclinical PDAC models. In summary, co-targeting PPARδ and oncogenic KRAS represents a mechanistically rational therapeutic approach to counteract PDAC metabolic plasticity, immune evasion, and therapeutic resistance, with the potential to achieve more durable treatment responses and improved clinical outcomes for patients with PDAC.

4.3.
PPARδ inhibition with immunotherapy
Despite advances in immunotherapy, PDAC remains resistant to immune checkpoint blockade due to its immunosuppressive and metabolically hostile iTME. Ligand-mediated PPARδ activation accelerates oncogenic KRAS-initiated pancreatic tumorigenesis and progression of PanINs to invasive PDAC [26]. In PanIN and PDAC cells, PPARδ activation induces secretion of CCL2, which recruits immunosuppressive macrophages and myeloid-derived suppressor cells through the CCL2/CCR2 axis. PPARδ also spatially restricts CD4⁺ and CD8⁺ T cells within the TME, further suppressing antitumor immunity [40]. In parallel, PPARδ reinforces pro-oncogenic signaling downstream of GOT2 [40], linking metabolic reprogramming to immune evasion. Therapeutically, pharmaceutical inhibition of PPARδ with antagonists and inverse agonists (e.g., GSK3787, DG172), in combination with immune checkpoint blockade including PD-1/PD-L1 antibodies (e.g., nivolumab, pembrolizumab) and CTLA-4 antibodies (e.g., ipilimumab) represent a promising strategy to reverse immune suppression and enhance the efficacy of immunotherapy in PDAC.

5.
Summary and perspectives
In summary, emerging evidence positions PPARδ as a primary regulator that amplifies oncogenic KRAS signaling and orchestrates metabolic adaptation, immune suppression, and therapeutic resistance throughout PDAC evolution. Recognizing PPARδ not merely as a metabolic modulator but as a central tumor accelerator reframes our understanding of PDAC biology and opens new avenues for intervention. Targeting PPARδ-centered networks, particularly in rational combination with KRAS-directed and immune-based therapies, holds promise for overcoming longstanding barriers in PDAC treatment and may ultimately translate into more durable clinical responses for patients with this devastating disease.
Despite these advances, several critical knowledge gaps currently limit clinical translation. First, the cell type–specific functions of PPARδ within the complex PDAC ecosystem remain poorly defined. Future studies leveraging single-cell and spatial transcriptomic, epigenomic, and metabolomic approaches will be essential to map PPARδ-regulated programs across distinct tumor, stromal, and immune compartments and to delineate how PPARδ signaling is dynamically rewired during disease progression and therapy. Second, the molecular mechanisms by which PPARδ promotes resistance to KRAS inhibitors, chemotherapy, and immunotherapy remain largely unexplored. Defining how PPARδ-driven metabolic and transcriptional programs buffer oncogenic stress and blunt therapeutic responses will be critical for rational combination strategies.