Effects of FAP+ cancer-associated fibroblasts on anti-PD-1 immunotherapy and CD4+ T cell polarization in gastric cancer.

Aim: The immune evasion mechanisms of gastric cancer are complex, involving various cellular dysfunctions within the tumor microenvironment. Recently, there has been growing interest in how cancer-associated fibroblasts (CAFs) contribute to tumor immune evasion. However, the precise molecular pathways through which CAFs drive immune escape in the context of gastric cancer are not yet fully elucidated. Methods: The abundance of FAP⁺CAFs in gastric cancer tissues was assessed by immunohistochemistry (IHC), and its correlation with tumor sensitivity to PD-1 monoclonal antibody therapy was analyzed. To study the effect of FAP⁺CAFs on naive CD4⁺ T cell differentiation, co-culture experiments were conducted. The underlying molecular mechanisms were further investigated through western blotting and in vivo animal experiments. Results: FAP⁺CAFs were significantly increased in gastric cancer tissues resistant to PD-1 monoclonal antibody, and a positive correlation was found with Th2 cells. Additionally, the expression and secretion of IL-31 in FAP⁺CAFs cells were elevated. Mechanistically, IL-31 interacts with the IL-31R expressed on naive CD4⁺ T cells, leading to the activation of the STAT6 signaling pathway. This cascade facilitates the differentiation of naive CD4⁺ T cells into Th2 cells, thereby contributing to resistance against anti-PD-1 therapy in gastric cancer. Conclusion: FAP⁺CAFs may reduce sensitivity to anti-PD-1 therapy in gastric cancer by promoting Th2 polarization of naive CD4⁺ T cells via the IL-31/STAT6 signaling pathway. Targeting this axis could offer a potential strategy to improve immunotherapy outcomes, although further validation is required.