PLA2G2A context dependence begins with its dual molecular identity. As an enzyme, sPLA2-IIA hydrolyzes phospholipids and increases local availability of AA and lysophospholipids^[1-3]. These products can feed prostaglandin, leukotriene and oxylipin pathways. In drug-resistant tumors, this catalytic output may amplify inflammatory survival signaling, stromal activation, myeloid skewing or T-cell dysfunction. The relevant therapeutic implication is that PLA2G2A expression alone cannot predict whether direct enzyme inhibition, downstream COX/PGE2 blockade, LOX-axis targeting or stromal-state modulation will be most rational.

Several studies show that sPLA2-IIA also has signaling outputs that cannot be reduced to catalysis. Exogenous sPLA2-IIA, including catalytically inactive variants, can promote PLA2G2A promoter activity through the M-type receptor and heparan-sulfate proteoglycans (HSPGs), creating autocrine or paracrine amplification loops^[4,5]. Lung and prostate cancer models link sPLA2-IIA to HER/ERBB-driven stem-like phenotypes^[6]. Direct integrin binding has been demonstrated for alpha-v beta-3, alpha-4 beta-1 and alpha-5 beta-1 in biochemical and inflammatory-cell systems^[7], while vimentin-associated trafficking suggests additional non-catalytic signaling routes^[8]. More recently, structure-informed cyclic peptides targeting human group IIA secreted phospholipase A₂ (hGIIA)-epidermal growth factor receptor (EGFR) and hGIIA-vimentin interactions provided preclinical proof-of-concept that protein-protein interactions can be pharmacologically separated from catalytic inhibition in prostate cancer models^[9]. We did not identify a cancer study that cleanly compares wild-type and catalytically inactive PLA2G2A while holding cell source, localization and receptor-binding context constant.

PLA2G2A expression integrates inflammatory, differentiation, endocrine, and metabolic inputs. Inflammatory regulation of PLA2G2A is context-dependent: elements of C/EBP, NF-κB, and Ets promoters participate in autocrine control in vascular smooth-muscle models^[4]. However, IFN-γ-induced expression has been linked to STAT3 activation and is further modulated by the surrounding cytokine milieu^[10]. NFATc2-containing circuitry extends induction downstream of C/EBP in hepatocyte models^[11]. Conversely, thyroid hormone receptor β can repress PLA2G2A transcription, and PPAR-family effects are model-dependent rather than uniformly activating or inhibitory^[5,12,13]. Thus, PLA2G2A is often a readout of the tissue state rather than an isolated driver.

The ability of sPLA2-IIA to reinforce its own expression through the M-type receptor, HSPG, and cPLA2-linked circuitry is therapeutically relevant^[4,5]. PPARα participates in an autocrine loop in mesangial-cell models^[5], whereas other PPAR-family contexts can repress PLA2G2A^[12]; these observations must not be condensed into a universal PPAR → PLA2G2A directional relationship. Resistance-associated ecosystems commonly require sustained low-grade signaling rather than transient inflammatory spikes. A locally retained secreted enzyme that can reinforce its persistence may help stabilize a resistant niche, but such a possibility requires compartment-specific validation in cancer models.

Where PLA2G2A is retained may be more important than how much is expressed. In atherosclerotic lesions, group IIA phospholipase A2 colocalizes with decorin, and decorin promotes collagen binding and enhances enzymatic activity^[14]. A similar principle may apply to ECM-rich cancers: desmoplastic stroma, invasive fronts and peritumoral adipose tissue can convert a secreted molecule into a spatially restricted signaling reservoir. Bulk RNA or serum protein levels may therefore underrepresent biologically active matrix-retained PLA2G2A.

The downstream map remains incomplete. EGFR/HER-family associations, HSPG-dependent amplification, direct integrin binding and vimentin-associated localization suggest candidate links to adhesion, receptor clustering, internalization, mitogen-activated protein kinase (MAPK), PI3K-AKT, FAK/Src and NF-κB programs^[6-9,14]. These should be presented as testable axes rather than as established pan-cancer mechanisms. The distinction is critical because a negative result with a catalytic inhibitor would not exclude non-catalytic PLA2G2A biology [Figure 1].

A major limitation of pan-cancer biomarker interpretation is the assumption that high PLA2G2A is uniformly adverse. Gastric cancer illustrates the opposite possibility. PLA2G2A was identified as a β-catenin/TCF target that suppresses invasion and metastasis in experimental models^[15], and clinical studies associated its expression with favorable histologic features, reduced metastasis and prolonged survival^[16,17]. These findings support a differentiation-associated epithelial program, although they do not prove independent causal protection after adjustment for tumor grade, stage, histologic subtype and immune infiltration.

Intestinal models add a barrier-protective configuration. PLA2G2A can suppress tumorigenesis in Muc2-deficient and azoxymethane-treated mice and is associated with goblet-cell expression and mucus- and microbial-defense-related programs^[18,19]. In cholangiocarcinoma, epigenetic repression of PLA2G2A can accompany progression in some contexts^[20]. These examples argue that direct PLA2G2A blockade could be undesirable when the dominant biology is epithelial differentiation, antimicrobial defense or barrier maintenance.

PLA2G2A has to be interpreted within a broader secreted phospholipase A2 family, but comparator isoforms are to be judged based on the same source-niche-output-function questions rather than by looser narrative criteria^[3]. In ovarian cancer, PLA2G3 provides tumor-cell source and PLA2G3-specific loss-of-function linked to lipid-droplet biology, metastasis and platinum sensitization, although spatial niche annotation is limited^[21]. In Epstein-Barr virus-associated B-cell lymphoma, macrophage-associated PLA2G10 is localized to an extracellular-vesicle niche, hydrolyzes EV phospholipids to generate fatty acids, lysophospholipids, and lipid mediators, and promotes lymphoma growth^[22]. In other tumor models, PLA2G10-mediated lipid hydrolysis impairs T-cell infiltration and confers resistance to anti-PD-1 therapy, providing a comparatively direct source-lipid-output-immune-function-therapy chain^[23]. PLA2G1B has a well-defined pancreatic-acinar source and intestinal/systemic lipid-output biology, but its cancer-relevant evidence remains less directly compartment-resolved^[24].

These comparisons show that context dependence, lipid-output specificity, and therapeutic redundancy are family-level rather than unique properties of PLA2G2A. We therefore do not claim PLA2G2A to be structurally unique among sPLA2 isoforms. Its relevance to the present review is the combination of ECM retention, M-type receptor/HSPG/integrin/vimentin interactions, and protective intestinal or barrier-associated configurations documented among distinct experimental systems^{[3,4,5,7,8,14]}. Direct PLA2G2A-specific evidence for tumor-associated macrophage polarization beyond the ovarian ascites setting, or for tumor-endothelial dysfunction and vascular normalization, remains sparse. Future studies must parallely quantify multiple sPLA2 isoforms and apply the same four-domain annotation to test redundancy, compensation, and isoform-specific druggability.

The most intuitive route from PLA2G2A to therapy resistance is lipid-mediator rewiring. By releasing AA, PLA2G2A can increase substrate availability for COX and LOX enzymes^[1-3]. COX/PGE2-rich tumor states can impair dendritic-cell function, promote myeloid skewing, restrain cytotoxic T-cell activity and support tumor-promoting inflammation^[25]. PLA2G2A is unlikely to be the sole determinant of this axis, and the cancer evidence map shows that direct PLA2G2A-linked lipid products are rarely measured in the same specimen or model [Table 2]. Accordingly, lipid-mediated resistance should not be inferred from PLA2G2A expression alone.

For therapeutic design, the distinction between upstream enzyme expression and downstream lipid output is essential. If PLA2G2A mainly supplies substrate to a COX/PGE2-dominant niche, downstream lipid-pathway blockade may be more rational than direct PLA2G2A inhibition. If its dominant role is receptor or matrix coupling, catalytic inhibition alone may fail. Therapy-oriented studies should therefore pair source-resolved PLA2G2A measurements with direct lipidomics when a lipid mechanism is proposed, receptor or ECM markers when non-catalytic biology is proposed, and immune-functional endpoints [Figure 2].

The strongest resistance-proximal PLA2G2A-specific evidence comes from fibroblast-rich PDAC. CAFs regulate ECM architecture, cytokine gradients, immune-cell trafficking, and treatment resistance^[26,27]. In PDAC, PLA2G2A-positive metabolic CAFs suppress CD8⁺ T-cell antitumor activity, reduce IFN-γ and granzyme B secretion, and impair cytotoxic function as well as MAPK/extracellular signal-regulated kinase (ERK) and NF-κB signaling in T cells^[28]. As this study demonstrates PLA2G2A-specific immune dysfunction without testing the outcome to a defined anticancer therapy, it is classified as M-A/R2 rather than as direct therapy-response evidence. The therapeutic point is that CD8⁺ T cells may remain but are functionally disabled; it differs from simple lymphocyte exclusion and implies that treatments aimed only at T-cell recruitment may be insufficient. A rational preclinical strategy would combine CAF-state modulation, recovery of T-cell effector signaling and checkpoint blockade, with spatial CAF-CD8 proximity and T-cell functional markers as pharmacodynamic readouts.

Ovarian cancer illustrates a fluid-phase lipid niche. Ovarian-cancer ascites contain abundant AA, and phosphoproteomics identified PLA2G2A as a clinically relevant extracellular enzyme associated with this pool^[29]. In macrophages, AA activated Ca²⁺/CaMKII-ASK1-p38 signaling, induced a stress program associated with poor outcome, impaired actin-driven macropinocytosis, and enhanced release of tetraspanin-containing vesicles^[29]. The study therefore supports AA-induced vesicle release; it does not establish that these vesicles are themselves AA-rich. Such evidence should be framed as a mechanistic association across linked but not fully PLA2G2A-perturbed steps rather than definitive proof of PLA2G2A alone driving ovarian immune escape. Direct PLA2G2A perturbation across the complete pathway is imperative. Nonetheless, the model suggests that ascite PLA2G2A activity, arachidonic-acid abundance, macrophage stress programs, and vesicle-release phenotypes could be co-evaluated in therapy-response studies.

Barrier tissues provide the clearest example of opposing PLA2G2A outputs. In the homeostatic intestine, PLA2G2A can contribute to mucosal protection and antimicrobial or microbial-defense programs^[18,19]. During chronic inflammatory injury, however, the same barrier-associated program may coexist with dysbiosis, cytokine exposure and tissue repair signals that condition future tumor immunity.

Human colon organoids exposed to pro-inflammatory conditions show increased PLA2G2A together with impaired barrier programs, whereas a multi-mineral intervention reduces PLA2G2A and improves epithelial cohesion and transepithelial resistance^[30]. Intestinal sPLA2-IIA can also reshape distant skin carcinogenesis by modifying the gut microbiota^[31]. These findings argue against default systemic PLA2G2A blockade in barrier organs; in selected settings, barrier repair or microbiota-aware intervention may be more rational.

Therapy and invasion expose cell states that may be missed by treatment-naive bulk profiling. In oral squamous-cell carcinoma (OSCC), single-cell and spatial multi-omics identified an ADH1B/MFAP4/PLA2G2A fibroblast subgroup positioned near invasive epithelial programs characterized by copy-number instability, glycolysis, hypoxia, reactive-oxygen-species adaptation and epithelial-mesenchymal transition^[32]. This suggests that PLA2G2A-positive fibroblasts may mark a boundary-zone stromal state where tissue repair, oxidative stress and invasive selection pressure converge.

Single-cell analyses of tyrosine kinase inhibitor (TKI)-treated lung cancer reveal stage-dependent stromal remodeling, with resistant lesions dominated by periostin (POSTN)-positive CAFs and ACKR1-positive endothelial cells^[33]. Any PLA2G2A-related CAF signal in this setting should therefore be interpreted as a candidate transitional feature rather than as a validated recurrent resistance marker. Longitudinal sampling is essential to distinguish adaptive remodeling from stable resistance architecture.

A broader lipid-niche model is needed because PLA2G2A acts in environments where extracellular lipid availability, adipocyte biology, inflammation and vesicular communication intersect. Reviews of cancer lipid metabolism emphasize that tumor lipid states are shaped by cell-extrinsic nutrients, adipocytes, stromal cells, hypoxia and physical TME features, and that lipid availability can propagate metabolic ripple effects beyond canonical lipid pathways^[34,35]. In this setting, PLA2G2A is best viewed as a potential amplifier of a lipid-rich inflammatory niche rather than as a sole upstream driver.

Adipocytes and adipose-associated stromal or immune cells can supply fatty acids, inflammatory cytokines and EVs, while EVs can package enzymes, lipids and matrix-interacting proteins. PLA2G2A in this context may indicate a secretory lipid-processing state that couples adipose inflammation, myeloid remodeling, mucin production or ECM remodeling. The interpretation remains hypothesis-generating unless PLA2G2A is spatially localized, lipid products are quantified and perturbation changes EV composition, macrophage state, CAF behavior or treatment response.

Gastrointestinal tumors demonstrate why PLA2G2A must be interpreted by compartment, phenotype, and evidence axis. In gastric cancer experimental models, epithelial PLA2G2A suppresses invasion and metastasis^[15], providing M-A evidence for an invasion-restraining phenotype, while patient cohorts associate PLA2G2A expression with favorable clinicopathologic features and survival^[16,17], which remains M-C clinical evidence. A gastric-cancer coexpression meta-network places PLA2G2A within a broader epithelial program^[36]. None of these studies directly establish therapy resistance (R0). CRC contains both protective and tumor-supportive configurations. In mouse models, PLA2G2A can protect against colorectal tumorigenesis when integrated with mucus and antimicrobial programs^[18,19]. In sporadic colorectal adenocarcinoma, bulk PLA2G2A expression is not uniformly enhanced compared with normal mucosa^[37], implying that average tissue expression may miss disease states in which PLA2G2A gains therapeutic relevance.

Mucinous colon adenocarcinoma illustrates why PLA2G2A-specific perturbation and whole-EV pathway evidence must be separated. Serum-derived EV proteomics demonstrated PLA2G2A enrichment in mucinous compared with nonmucinous tumors^[38]. In a separate PLA2G2A-specific experiment, PLA2G2A overexpression in SW480 cells enhanced migration and invasion. By contrast, Wnt/β-catenin and other changes in cancer-related pathways were derived from recipient cell proteomics after stimulation with whole mucinous-cancer EVs and therefore cannot be attributed specifically to PLA2G2A^[38]. Any direct PLA2G2A-linked AA, PGE2, oxylipin, or lysophospholipid measurement was not reported in that model. These data support M-A evidence for migration/invasion and M-B proof for the EV compartment, but R0 for direct treatment resistance.

Hepatobiliary evidence is heterogeneous. Gallbladder-carcinoma single-cell analysis identified PLA2G2A-positive epithelial states and included PLA2G2A overexpression showing elevated proliferation and stemness, reduced apoptosis and, crucially, declined migration/invasion within the tested cell models^[39], constituting M-A functional but not therapy-response evidence (R0). PLA2G2A has been proposed as a diagnostic or prognostic biomarker for cholangiocarcinoma^[40], whereas epigenetic data indicate that PLA2G2A repression may accompany progression within certain contexts^[20]. In inflammatory hepatocellular adenoma, PLA2G2A marks an inflammation-rich subtype^[41]. These divergent observations support stage- and phenotype-dependent interpretation rather than a static tumor-promoting model.

PDAC is currently the most compelling setting for a causal stromal immune-dysfunction model. PLA2G2A-positive metabolic CAFs suppress CD8⁺ T-cell effector function through MAPK/ERK and NF-κB inhibition, reduce effector cytokines and blunt tumor killing^[28]. This places PLA2G2A within a stromal immune-escape program rather than a tumor-cell-autonomous oncogene. Under the revised framework, the study is M-A/R2: PLA2G2A-specific functional evidence is strong, but a defined anticancer therapy-response experiment was not performed. Independent cohorts, orthogonal spatial proteomics, lipidomic readouts and immunocompetent therapy-response models are needed before extrapolation to other tumors.

Squamous tumors add spatial and therapy-stage nuance. In OSCC, PLA2G2A-positive fibroblasts may identify an invasive-front branch point where tissue-preserving stromal functions are co-opted into tumor-supportive ecology^[32]. In recurrent or metastatic head and neck squamous-cell carcinoma (HNSCC) treated with dacomitinib, exploratory biomarker analysis linked high inflammatory gene-expression signals, particularly cytokine-centered programs, with shorter progression-free survival^[42]. These observations are compatible with a resistance-associated inflammatory niche, but they do not establish PLA2G2A-specific druggability.

In lung squamous-cell carcinoma, loss of representative tumor-suppressor genes was associated with a colder microenvironment and reduced expression of immune-system-related genes including PLA2G2A^[43]. Thus, diminished PLA2G2A is not automatically favorable; in specific squamous ecosystems, it may accompany the collapse of productive immune-stromal crosstalk. Both high- and low-intensity PLA2G2A signals therefore require context-resolved interpretation. In prostate cancer, PLA2G2A must be treated as a limited-evidence-value, endocrine-sensitive signal rather than a validated stromal driver. Cell-line data suggest that 5α-reductase suppression can alter gene-expression programs including PLA2G2A^[44]. Prognostic and immune-infiltration analyses associate PLA2G2A-containing signatures with an immune context and outcome^[45,46]; a 5′ UTR polymorphism is linked to metastatic risk^[47]. Preclinical protein-protein interaction inhibitors provide a mechanistic model for noncatalytic targeting^[9], but clinical applicability remains unresolved.

Renal and bladder cancers provide mostly correlative evidence. In clear-cell renal-cell carcinoma, one immunogenomic analysis constructed an immune-related prognostic model that included PLA2G2A among prognostic immune-system-related genes^[48]. A separate TCGA/SEER study addressed another question - age stratification and age-related differentially expressed genes - and identified PLA2G2A as an age-associated gene linked to poorer prognosis in older patients rather than as an immune-risk model^[49]. Separate studies on ferroptosis and glutathione indicate that redox adaptation is relevant in ccRCC, but these data are not PLA2G2A-specific^[50]. In bladder cancer, PLA2G2A is incorporated into lipid-metabolism signatures associated with prognosis, immune infiltration, and predicted immunotherapy response^[51]. These reports support stratification hypotheses but do not justify PLA2G2A as an independent therapeutic target.

Endometrial cancer studies repeatedly place PLA2G2A within immune-risk classifiers that stratify survival, tumor mutation burden, immune infiltration, and predicted response to immuno- or chemotherapy^[52,53]. The signal appears to reflect immune-state organization rather than uniform tumor-cell overexpression. These signatures may be clinically applicable for risk stratification, but cannot distinguish whether PLA2G2A is a driver, an inflammatory passenger, or a surrogate for immune-cell composition. Breast cancer underscores compartmental divergence. Single-cell profiling of primary tumors and paired lymph-node metastases identified a PLA2G2A-positive CAF subset enriched in HER2-positive disease and interacting with T cells, dendritic cells, and macrophages^[54]. By contrast, experimental breast-cancer models implicate a PLA2G2A/DCN axis in stachydrine-associated growth restraint^[55], reinforcing the core principle that epithelial and stromal PLA2G2A should not be merged for biological relevance.

Ovarian cancer represents a secretory lipid-milieu configuration. Ascites-derived AA is clinically adverse, and PLA2G2A is implicated as an extracellular enzyme contributing to this lipid pool^[29]. The downstream macrophage findings are AA-driven, including stress signaling, impaired macropinocytosis, and AA-induced release of tetraspanin-containing vesicles; the study does not show that those vesicles are AA-enriched. Direct PLA2G2A perturbation, paired ascites lipidomics, and macrophage-state readouts are needed to move this setting from compartment-linked association toward therapeutic causality.

Bulk RNA or serum PLA2G2A assessments alone are unlikely to be clinically interpretable. A therapy-relevant biomarker should distinguish epithelial vs. stromal source, tissue-retained vs. circulating or EV-associated pools, tumor core vs. invasive-front localization, and treatment-naive vs. therapy-remodeled states. The study-level evidence and the occurrence of direct lipid-output measurements are summarized in Table 2. Without these distinctions, PLA2G2A may appear inconsistent across studies as assays measure varied biological compartments and evidence domains.

A minimum prospective biomarker panel must include PLA2G2A source compartment, CAF or epithelial markers, and a mechanism-matched output. When a catalytic lipid mechanism is proposed, it has to include direct AA/PGE2/oxylipin or lysophospholipid assessments rather than inferred pathway activity. When an immune mechanism is proposed, markers such as IFNG, GZMB, CD69, and OX40 in CD8⁺ T cells and relevant myeloid stress markers must be quantified. Longitudinal studies have to sample the same markers before treatment, during response, and at progression to determine whether PLA2G2A marks a transient remodeling window or a stable resistance state.

The evidence argues against a one-size-fits-all PLA2G2A inhibitor strategy. In a catalytic lipid-dominant context, downstream COX/PGE2 or LOX-axis blockade may be more rational than direct PLA2G2A inhibition. In a CAF-dominant context, fibroblast-state modulation plus T-cell reactivation may be worth testing as a preclinical combination hypothesis. In a secretory lipid niche such as ovarian ascites, macrophage-state reprogramming and lipid-axis blockade require direct validation. In barrier organs, restoring epithelial integrity or microbiota balance may be preferable to direct PLA2G2A blockade. These scenarios should be treated as mechanism-matched trial-enabling hypotheses, not as immediate clinical recommendations.

Mechanistic matching is especially important because sPLA2-IIA can signal through M-type receptor and HSPG-dependent amplification^[4,5], direct integrin binding^[7], EGFR/HER-family or vimentin-associated interactions^[6,8,9], and matrix retention^[14]. A prognostic association does not justify targeting unless perturbation changes the relevant immune, lipid, stromal or therapy-response phenotype. Peritumoral adipose fibrosis and microsatellite instability-high (MSI-H)/mismatch-repair deficient (dMMR) anti-PD-1 nonresponse provide additional TME contexts in which the potential contribution of PLA2G2A should be investigated directly rather than assumed^[56,57].

A major translational bottleneck is the absence of a clinically approved PLA2G2A-specific anticancer inhibitor. Varespladib/varespladib methyl inhibits multiple secreted PLA2 isoforms^[3] and has been clinically evaluated outside oncology; in acute coronary syndrome, the VISTA-16 randomized trial did not support benefit and raised safety concerns^[58]. Systemic catalytic blockade therefore cannot be proposed as a straightforward cancer strategy without patient selection, pharmacodynamic monitoring and tissue-specific safety assessment.

Non-catalytic targeting remains clinically immature. Cyclic peptides that interfere with hGIIA-EGFR and hGIIA-vimentin interactions provide preclinical proof-of-principle^[9], but their applicability outside prostate cancer is unknown. Compartment-restricted strategies such as local delivery, ascites-directed intervention, CAF-targeted carriers, ECM-activated prodrugs or EV-associated capture remain experimental concepts. Validation should include enzyme activity, protein-protein binding, spatial pharmacodynamics, lipidomics, immune readouts and barrier-toxicity assays.

The field now needs fewer bulk-expression catalogs and more mechanism-matched validation. Key questions include which PLA2G2A-positive cell states are functionally immunosuppressive, which are protective or reactive, which outputs depend on catalytic lipid release, and which depend on receptor or matrix coupling. It is also essential to test whether spatial biomarkers can identify patients whose tumors are truly PLA2G2A-dependent and whether PLA2G2A marks an early remodeling window that can be interrupted before terminal resistance architecture develops. These priorities are summarized with study-specific evidence codes and citations in Table 3.