Abstract Chemotherapy resistance remains the primary cause of treatment failure in pancreatic ductal adenocarcinoma (PDAC). Therapy induced tumor dormancy enables tumor cells escape from chemotherapy cytotoxicity. Our study reveals that gemcitabine treatment triggers extracellular matrix (ECM) fibrosis and collagen rearrangement, with significant accumulation of type III Collagen (COL3). Crucially, exogenous COL3 supplementation in subcutaneous and orthotopic PDAC models could induce tumor cell dormancy accompanied by p21/p27 upregulation and promote chemoresistance. Meanwhile, COL3 enrich tumor-associated macrophages (TAMs) within chemoresistant niches. Mechanistically, COL3 induction was driven by CREB3L1-activated unfolded protein response (UPR) during chemotherapy stress. CREB3L1 regulated dormancy associated molecules like COL3, p21 and p27 and remodeled the stromal microenvironment. These findings establish COL3 as a central mediator of PDAC chemoresistance by orchestrating dormancy and immunosuppressive niche formation. Targeting the CREB3L1-COL3 axis represents a promising strategy to overcome acquired resistance in pancreatic cancer. Citation Format: Haiyan Xu, Yicheng Zhou, Shengbai Xue, Siming Wu, Liwei Wang. Type III collagen regulated by stress signaling drives chemoresistance in pancreatic cancer by inducing tumor dormancy and remodeling the immunosuppressive niche abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3447.
Xu et al. (Fri,) studied this question.