RANKL/PD-1 dual blockade demonstrates survival benefit for patients with advanced lung adenocarcinoma harboring KRAS mutations.

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 prospecti

SUBMITTER: Li HS 

PROVIDER: S-EPMC12281428 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature