Abstract 2170: S100a6-Lars2 oncogenic signaling shaping immunosuppressive environment contributes to platinum-based resistance

Abstract Chemotherapy-induced drug resistance is a very complex process. About 20% of cancer patients have received effective therapy with platinum (Pt) medicines, and drug resistance has since emerged through several mechanisms. To investigate the complicated heterotypic interactions between cancer cells and immune cells during the resistant tumor outgrowth processes under Pt treatment, we dissected the crosstalk signals with single-cell RNA sequencing and performed functional studies on Pt-induced drug resistance using overexpression, knockout, and DOX-inducible technologies. In this study, we have identified that: 1) S100a6-Lars2 oncogenic signaling could promote TGF-β production from tumor and immune cells and induce expressions of PD1, Tim3, and Selplg on T cells, which could contribute to resistant tumor outgrowth under Pt treatment; 2) Pt drugs could promote the survival of cancer stem cells (CSCs) with elevated hyaluronan-mediated motility receptor (Hmmr) and mTOR oncogenic pathway; 3) we validated Lars2 oncogenic action in resistant tumor outgrowth in FVB immunocompetent mice and the dynamic changes of the immune cell population; 4) combinatory treatment involving the inhibition of TGF-β signaling, the mTOR pathway, and Hmmr action, along with PD1 antibody, shows a significant effect in inhibiting tumor growth. This study advances the understanding of the mechanism of Pt drug-induced resistant tumor outgrowth, which may allow us to better manage the tumor immune microenvironment (TIME) and postpone the onset of resistance. Citation Format: Yuqing Wang, Chuxia Deng. S100a6-Lars2 oncogenic signaling shaping immunosuppressive environment contributes to platinum-based resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2170.