FAP upregulates PD-L1 expression in cancer-associated fibroblasts to exacerbate T cells dysfunction and suppress anti-tumor immunity.

FAP-positive cancer-associated fibroblasts (CAFs), recognized as a critical subset of CAFs, have been implicated in fostering an immunosuppressive tumor microenvironment in various cancers. However, their potential mechanisms of immunosuppression, particularly in modulating T cells, remain elusive. In this study, multiple internal cohorts consisting of 328 patients as well as 5 external cohorts were integrated to delineate the association between unfavorable prognosis or therapeutic resistance and FAP CAFs in gastric cancer patients. Subsequently, using in vivo mice models and in vitro co-culture system, we found that elevated infiltration levels of FAP CAF exacerbated immunosuppression in the tumor microenvironment by facilitating CD8 T cells dysfunction. Mechanistically, FAP impeded the degradation of STAT1 protein in CAFs, thereby sustaining PD-L1 transcription and fostering T cell exhaustion. Treatment with PD-L1 neutralizing antibodies effectively attenuated FAP-mediated immunosuppression, restoring anti-tumor immunity of T cells. Overall, our findings underscore the vital role of FAP CAFs in directly suppressing T cell-mediated anti-tumor immunity via PD-L1 upregulation, paving the way for the development of FAP-targeted therapies in clinical settings.