Abstract
Preclinical/clinical studies suggest that receptor activator of nuclear factor κB (NF-κB) ligand (RANKL) inhibitors combined with immune checkpoint inhibitors (RLICi) enhance anti-tumor efficacy in lung adenocarcinoma (LUAD), yet mechanisms remain unclear. Our retrospective cohort demonstrates RLICi superiority in Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutant LUAD. Transcriptomics reveal that RANKL upregulation was inversely correlated with PD-L1 and CXCL9/10/11 levels, suppressing CD8+ T cell infiltration via phosphatidylinositol-3-kinase/AKT serine/threonine kinase-mediated PD-L1 downregulation and macrophage chemokine reduction. In murine models, RLICi outperform PD-1 monotherapy, augmenting M1 macrophage recruitment and CD8+ T cell influx. The prospective DEMAIN trial validates RLICi clinical efficacy. This study elucidates RANKL-driven immunosuppression in KRAS-mutant LUAD and establishes RLICi as a viable therapeutic strategy for this subset. The trial was prospectively registered in the Chinese Clinical Trial Register (registration number: ChiCTR2100047759).