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

Rongyuan Wei; Junquan Song; Chenchen Liu; Zhenxiong Zhao; Xuanjun Liu; Masami Yamamoto; Tetsuya Tsukamoto; Sachiyo Nomura; Fenglin Liu; Yanong Wang; Xiaowen Liu

doi:10.1016/j.canlet.2025.217475

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

Cancer Lett. 2025 Jan 18:217475. doi: 10.1016/j.canlet.2025.217475. Online ahead of print.

Authors

Affiliations

¹ Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College of Fudan University, Shanghai, China.
² Department of Plastic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
³ Department of Applied Science, School of Veterinary Nursing and Technology, Nippon Veterinary and Life Science University, Tokyo, Japan.
⁴ Department of Diagnostic Pathology, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.
⁵ Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
⁶ Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College of Fudan University, Shanghai, China. Electronic address: [email protected].
⁷ Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College of Fudan University, Shanghai, China. Electronic address: [email protected].
⁸ Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College of Fudan University, Shanghai, China. Electronic address: [email protected].

PMID: 39828123
DOI: 10.1016/j.canlet.2025.217475

Abstract

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.

Keywords: Cancer-associated fibroblasts; FAP; Gastric cancer; Immunosuppression; PD-L1; T cells dysfunction.