2. Academic Validation
  3. BFAR promotes neutrophil infiltration and immunosuppressive reprogramming through the PRP19-YBX1 axis to induce immune evasion in gastric cancer

BFAR promotes neutrophil infiltration and immunosuppressive reprogramming through the PRP19-YBX1 axis to induce immune evasion in gastric cancer

  • Cancer Immunol Res. 2025 Sep 18. doi: 10.1158/2326-6066.CIR-24-1011.
Xin Ma # 1,  Yumei Liu # 2,  Yingying Chen 1,  Juan Wang 1,  Feiyue Zhang 1,  Wei Liang 3,  Pengbo Zhang 4,  Yunlan Zhou 5,  Bei Miao 1,  Sujuan Fei 1,  Masami Yamamoto 6,  Tetsuya Tsukamoto 7,  Sachiyo Nomura 8,  Li Li 9,  Jiajia Wang 10
Affiliations

Affiliations

  • 1 Department of Gastroenterology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
  • 2 Huadong Hospital, China.
  • 3 Shanghai Clinical Research Center, China.
  • 4 Department of General Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
  • 5 Xin Hua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 6 Nippon Veterinary and Life Science University, Japan.
  • 7 Fujita Health University, Aichi, Japan.
  • 8 Hoshi University, Shinagawa-ku, Tokyo, Japan.
  • 9 Department of Gastroenterology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China. lily9711214@126.com
  • 10 XinHua Hospital, Shanghai, China. wangjiajia@xinhuamed.com.cn
  • # Contributed equally.
PMID: 40966304 DOI: 10.1158/2326-6066.CIR-24-1011
Abstract

The immunosuppressive tumor microenvironment (TME) remains a major barrier to effective immunotherapy in gastric Cancer (GC). Here, we identified the E3 ubiquitin Ligase BFAR as a critical regulator of neutrophil-mediated immune evasion through the S100A8/A9-BFAR-PRP19-YBX1 signaling axis. Multi-omics analyses revealed that BFAR is overexpressed in GC and correlates with poor prognosis. Functional studies demonstrated that BFAR knockdown suppressed tumor growth by reducing neutrophil infiltration and immunosuppressive reprogramming to restore CD8+ T cell function. Mechanistically, BFAR mediated K48-linked ubiquitination and degradation of PRP19, leading to stabilization of the oncoprotein YBX1, which transcriptionally upregulated neutrophil-recruiting chemokines CXCL1/CXCL3. Infiltrating neutrophils secreted S100A8/A9, which activated NF-κB to induce BFAR expression in tumor cells and created a feedforward loop that sustains an immunosuppressive TME. Furthermore, BFAR promoted neutrophil PD-L1 expression via GM-CSF, reinforcing T cell exhaustion. Clinically, BFAR expression correlated with neutrophil infiltration and poor response to anti-PD-1 therapy, while its inhibition synergizes with immune checkpoint blockade in preclinical models. Our work unveils BFAR as a central orchestrator of neutrophil-driven immunosuppression and proposes targeting this axis to enhance immunotherapy efficacy in GC.

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