Ma X, Liu Y, Chen Y, Wang J, Zhang F, Liang W, Zhang P, Zhou Y, Miao B, Fei S, Yamamoto M, Tsukamoto T, Nomura S, Li L, Wang J

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 ...

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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-?B 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.

Date: Sep. 18, 2025

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