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

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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 patients and mice. • Combination treatment of carboplatin together with TGF-β receptor inhibitor and αPD-1 impede LARS2 + tumor outgrowth.

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