CAFs-derived IL-6 remodels the immunosuppressive microenvironment via STAT3-mediated M2 polarization in gastric cancer

Background Cancer-associated fibroblasts (CAFs) remodel the immune microenvironment to drive gastric cancer progression, yet the precise molecular mechanisms remain unclear. This study aimed to elucidate how CAF-derived Interleukin-6 (IL-6) induces macrophage M2 polarization via the signal transducer and activator of transcription 3 (STAT3) axis to promote gastric cancer malignancy. Methods In vitro, macrophages were treated with CAF-conditioned medium or exogenous IL-6, with or without the STAT3 inhibitor Stattic. M2 polarization markers and immunosuppressive factors were assessed. Gain- and loss-of-function assays verified IL-6's role. In vivo, SGC-7901/CAF subcutaneous xenografts were established in BALB/c nude mice (n = 5 per group) to evaluate tumor growth, apoptosis, macrophage infiltration, STAT3 activation, and circulating cytokines. Results CAF-conditioned medium upregulated p-STAT3 nuclear translocation in macrophages, driving CD206 + M2 polarization and transforming growth factor-β (TGF-β)/IL-10 secretion; these effects were reversed by Stattic. IL-6 knockdown in CAFs attenuated M2 polarization, whereas exogenous IL-6 restored it. In vivo, co-injection of IL-6-knockdown CAFs with SGC-7901 cells significantly suppressed tumor growth, reduced Ki-67 proliferation index, and increased TUNEL-positive apoptosis. Furthermore, intratumoral F4/80 + CD206 + M2 macrophage density, p-STAT3 levels, and IL-6 expression were markedly downregulated. Serum IL-6 and TGF-β concentrations also decreased concomitantly. Conclusion CAFs promote gastric cancer progression by establishing a local immunosuppressive niche via the IL-6/STAT3-driven M2 macrophage polarization, accompanied by elevated circulating levels of key immunomodulatory cytokines. Targeting this axis effectively remodels the innate immune and stromal microenvironment, providing a potential therapeutic strategy to overcome stromal-mediated innate immune suppression.