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

作者：Hong‐Shuai Li, Chengming Liu, Sufei Zheng, Peng Wu, Hanyan Xu, Xuezhi Hao, Junling Li, Puyuan Xing, Jianchun Duan, Zhijie Wang, Jia Zhong, Linyan Tian, Yanyan Cui, Fang Qin, Siyu Lei, Sihui Wang, Yuejun Luo, Zhan-Yu Wang, Jie Wang, Jie He, Nan Sun, Yan Wang · 发表于：Cell Reports Medicine · 年份：2025 · DOI：10.1016/j.xcrm.2025.102235 · 被引用次数：6 · 研究领域：Lung Cancer Treatments and Mutations、Chronic Lymphocytic Leukemia Research、Cell death mechanisms and regulation

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).