RBM10 Deficiency Promotes Anti‐PD‐1 Resistance in LUAD via STING Alternative Splicing‐Driven CCL7 Signaling and Macrophage Polarization

ABSTRACT Although immune checkpoint inhibitors have improved outcomes in lung adenocarcinoma (LUAD), many patients still exhibit inadequate responses. The immunomodulatory functions of RNA‐binding motif (RBM) proteins remain poorly understood. Using in vivo and in vitro models of RBM10 deficiency combined with cytokine arrays, CLIP‐seq, RIP, and proteomics, we found that RBM10 deficiency promotes an immunosuppressive microenvironment, and targeting key chemokines restored anti‐PD‐1 efficacy in RBM10‐deficient LUAD models. RBM10 deficiency enhanced the polarization and recruitment of M2 tumor‐associated macrophages (TAMs), both in vitro and in vivo. Mechanistically, RBM10 loss disrupted STING exon 3 exclusion via alternative splicing and impaired QKI‐mediated stabilization of the STING‐E3(‐) isoform, shifting the splicing balance toward the STING‐E3(+) isoform and promoting CCL7 secretion. CCL7 acted through its receptor CCR2 on macrophages, driving M2 polarization and recruitment. This central pathway was further reinforced by a positive feedback loop wherein M2‐polarized TAMs transferred mitochondria to tumor cells, potentially contributing to mtDNA‐cGAS‐STING signaling and sustained CCL7 production. Therapeutically, CCL7/CCR2 blockade synergized with PD‐1 inhibition to promote tumor regression in RBM10‐deficient tumors. Collectively, RBM10 serves as a key immunoregulator in LUAD by modulating the STING‐CCL7‐CCR2 axis, and targeting the CCL7‐CCR2 axis represents a promising strategy to overcome anti‐PD‐1 resistance.