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

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

  • Cancer Lett. 2025 Mar 1:612:217475. doi: 10.1016/j.canlet.2025.217475.
Rongyuan Wei 1,  Junquan Song 2,  Chenchen Liu 1,  Zhenxiong Zhao 1,  Xuanjun Liu 1,  Masami Yamamoto 3,  Tetsuya Tsukamoto 4,  Sachiyo Nomura 5,  Fenglin Liu 6,  Yanong Wang 7,  Xiaowen Liu 8
Affiliations

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: fenglinliu@hotmail.com.
  • 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: drwangyn@126.com.
  • 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: liuxw1129@hotmail.com.
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.

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