Abstract 2593: Caspase-1 dependent pyroptosis converts αSMA+ CAFs into collagen-III high iCAFs to fuel chemoresistant cancer stem cells

Abstract Chemotherapy-induced pyroptotic tumor cells potentially impact on cancer-associated fibroblasts (CAFs), which serve as key cellular components in stroma to construct a favorable tumor microenvironment (TME). Our study identifies three CAFs subtypes: αSMA+IL-6- myofibroblastic CAFs (myCAFs), αSMA-IL-6+ inflammatory CAFs (iCAFs), and hybrid i/myCAFs. Caspase-1 activation in tumor cells release inflammatory chemokines/cytokines, promoting iCAFs formation in a CCR6-dependent manner. Interestingly, the reactive iCAFs, instead of myCAFs, contribute to collagen III expression upon chemotherapy-induced cancer cell pyroptosis. Collagen III-enriched microenvironment preferentially harbors CD44high cancer stem cells (CSCs). Consistently, chemoresistant bladder cancers enhance iCAFs markers and collagen III after neoadjuvant chemotherapy. Thus, chemotherapy-caused pyroptotic cancer cells initiates an iCAFs-CSCs feedforward loop to drive the formation of chemoresistant TME. Citation Format: Hongbo (Beth) Gao, Stephen Q.R. Wong, Ethan Subel, Mustafa Karabicici, Winston Huang, Mark Ellie Alonzo, Keith Syson Chan. Caspase-1 dependent pyroptosis converts αSMA+ CAFs into collagen-III high iCAFs to fuel chemoresistant cancer stem cells [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 2593.