Lars2-signaling mediates platinum resistance by accumulating cancer stem cell population and suppressing anti-tumor immunity

作者：Yuqing Wang, Min Deng, Josh Haipeng Lei, Kai Miao, Xiaodong Shu, Jianjie Li, Dongyang Tang, Yangyang Feng, Sek Man Su, Ling Li, Yanjie Wang, Heng Sun, Fangyuan Shao, Tingting An, Xiaoling Li, Fanlin Zhou, Tingxiu Xiang, Xiaoling Xu, Chuxia Deng · 发表于：Drug Resistance Updates · 年份：2025 · DOI：10.1016/j.drup.2025.101330 · 研究领域：Ferroptosis and cancer prognosis、Cancer Immunotherapy and Biomarkers、Cancer Cells and Metastasis

Platinum-based chemotherapy remains a cornerstone of cancer treatment; however, its clinical efficacy is frequently compromised by acquired drug resistance. Our study elucidated a novel resistance mechanism mediated by LARS2 signaling in mammary tumors. Through comprehensive multi-omics analyses of cancer patients, mouse models, and functional validation, we demonstrated that platinum treatment upregulates LARS2 via a danger-triggered host response during resistant tumor progression, concomitant with increased chromatin accessibility. This signaling drives drug resistance through two key mechanisms: enrichment of cancer stem cells and promotion of TGF-β-mediated immunosuppression, as evidenced by M2 macrophage polarization and CD8 + T cell exhaustion. Importantly, we developed an effective therapeutic strategy combining carboplatin with LARS2 signaling pathway inhibition, which successfully reversed platinum resistance and restored PD-1 checkpoint blockade sensitivity in preclinical models. These findings not only advance our understanding of chemotherapy resistance, but also provide a translatable therapeutic framework for breast cancer and other platinum-treated malignancies. • Pt-drug treatment induces LARS2 and promotes resistant tumor progression in both human cancer patients and mice. • LARS2-S100A6 oncogenic signaling induced by Pt accumulates CSCs and enhances resistant tumor outgrowth. • TGF-β butterfly effects caused by Pt enhances immune evasion in both cancer pati...