Disrupting SRSF10-dependent BCAT2 exon skipping reprograms tumor-associated macrophages and enhances anti-PD-1 efficacy in gastric cancer.

Aberrant alternative splicing (AS) in cancer generates oncogenic proteomic diversity that drives tumor progression. Given the suboptimal efficacy of immune checkpoint inhibitors (ICIs) in gastric cancer (GC), the therapeutic potential of modulating RNA splicing to augment immunotherapy remains unclear. Here, we demonstrate that the splicing factor SRSF10 is progressively upregulated during gastric tumorigenesis and exhibits elevated expression in ICIs-resistant GC. Utilizing multiple mouse models, we confirmed that SRSF10 ablation with a selective inhibitor 1C8 robustly inhibits GC growth and enhances CD8 T-cell infiltration via CCL2-mediated reprogramming of tumor-associated macrophages (TAMs). Notably, SRSF10 blockade restricts pre-neoplastic metaplastic cells re-entry the cell cycle and the TAMs reprogramming. Mechanistically, cell-autonomous SRSF10 activates mTOR signaling primarily through inclusion of exon 2 in the BCAA transaminase 2 (BCAT2) mRNA. Pharmacological antagonism of SRSF10 potentiated the therapeutic effect of anti-PD-1 antibody in Tff1-CreER; Apc; p53 orthotopic GC models. Collectively, our findings revealed that SRSF10 orchestrates mTOR-CCL2 signaling by alternative RNA splicing of BCAT2 to reprogram TAMs, proposing SRSF10 as a tempting therapeutic target for GC immunotherapy.