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

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.