Magnesium isoglycyrrhizinate remodels the inflammatory tumor microenvironment in gastric cancer through inhibition of the phospholipase A2 (PLA2)/nuclear factor κB (NF-κB)signaling axis

Background Chronic inflammation drives tumor progression by fostering an immunosuppressive tumor microenvironment (TME). Phospholipase A2 (PLA2) contributes to this process through the generation of bioactive lipid mediators. The present study investigated the efficacy and mechanism of magnesium isoglycyrrhizinate (MgIG), a clinical PLA2 inhibitor with anti-tumor potential, in remodeling the inflammatory TME of gastric cancer. Methods Murine gastric cancer (MFC) syngeneic allografts were established in mice to evaluate the anti-tumor effects of MgIG. Cell viability was examined in MFC and human gastric adenocarcinoma (AGS) cell lines. Cytokine and chemokine expression in the tumors was quantified by quantitative real-time polymerase chain reaction (qRT-PCR). Key immune cell infiltration within the TME was assessed via immunohistochemistry (IHC). Western blotting was used to investigate the downstream effects of MgIG on signaling pathways. Conditioned medium (CM) from MgIG-treated tumor cells was used to culture murine macrophage (RAW264.7) and human monocytic leukemia (THP-1) cell lines, and polarization markers were analyzed by western blotting, immunofluorescence (IF), and enzyme-linked immunosorbent assay (ELISA). Overexpression of phospholipase A2 group IVA ( Pla2g4a in MFC cells and PLA2G4A in AGS cells) was performed to validate the mechanistic pathway. Comparisons were performed using Student's t test or analysis of variance (ANOVA). Survival differences were assessed by the log-rank test. Results MgIG significantly suppressed the growth of MFC gastric cancer allografts, as evidenced by reduced tumor volume and weight (both P < 0.05). Additionally, it prolonged the survival of tumor-bearing mice ( P < 0.0001) without inducing hepatotoxicity or gastric tissue damage (ALT, P = 0.7482; AST, P = 0.3293). Mechanistically, MgIG induced treatment-specific regulation of inflammatory mediators within the TME, including reductions in the expression of C-X-C motif chemokine ligand 1 ( Cxcl1 ), interleukin 10 ( Il10 ), Il23a , and key nodes in the toll-like receptor 4 ( Tlr4 )/TLR6–myeloid differentiation primary response gene 88 ( Myd88 )–nuclear factor κB ( NF-κB ) pathway ( P < 0.05). Molecular docking suggested a potential interaction between MgIG and PLA2G4A, which was associated with the reduced activation of NF-κB pathway and p65 nuclear translocation ( P < 0.05). Furthermore, MgIG reshaped the immune landscape by increasing the infiltration of CD8 + T cells and macrophages while reducing regulatory T cell (Treg) infiltration ( P < 0.05). Crucially, CM from MgIG-treated tumor cells polarized tumor-associated macrophages (TAMs) from an M2-like toward an M1-like phenotype, characterized by elevated inducible nitric oxide synthase (iNOS) and IL-12A expression and decreased arginase-1 (Arg-1) and CD206 levels ( P < 0.05). This polarization shift was associated with PLA2–NF-κB signaling, as mouse Pla2g4a or human PLA2G4A overexpression reversed the MgIG-induced M1-like polarization ( P < 0.05). Conclusions MgIG suppresses gastric cancer progression by remodeling the inflammatory TME, thereby enhancing anti-tumor immunity and inhibiting immune evasion. MgIG enhances cytotoxic T-cell infiltration and, critically, reverses macrophage polarization from an M2-like to an M1-like phenotype, potentially via inhibition of the PLA2–NF-κB signaling axis, with associated suppression of the TLR–MyD88 pathway. These findings suggest that MgIG possesses immunomodulatory functions and indicate its potential as a therapeutic strategy for suppressing inflammation-driven gastric cancer, warranting further clinical investigation.