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

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.