Cancer-Associated Fibroblast Heterogeneity and Extracellular Matrix Remodeling as Orchestrators of Drug Resistance in Upper Gastrointestinal Cancers: Insights from Spatial Multi-Omics and Therapeutic Implications

Upper gastrointestinal (GI) cancers, including esophageal, gastric, and pancreatic cancers, remain among the most lethal malignancies worldwide, mainly because they resist nearly every therapeutic modality, from platinum-based chemotherapy, and anti-HER2 and anti-VEGF agents, to immune checkpoint inhibitors. Although tumor cell-intrinsic resistance is well characterized, an increasing share of treatment failure traces to the tumor microenvironment (TME), where cancer-associated fibroblasts (CAFs) and the extracellular matrix (ECM) act not as passive stroma but as active orchestrators of resistance. Here we argue that the functional heterogeneity of CAFs, spanning myofibroblastic (myCAF), inflammatory (iCAF), and antigen-presenting (apCAF) subtypes, and the desmoplastic ECM they construct converge on a small number of shared resistance programs. Those include paracrine signaling, metabolic reprogramming, extracellular vesicle (EV) transfer, and biomechanical remodeling that together drive chemoresistance, targeted therapy evasion, and immune exclusion. Emerging spatial multi-omics now resolves these programs to define niches within upper GI tumors, reframing resistance as a spatially organized property of the tissue rather than the tumor cell alone. We bring this evidence together and evaluate strategies aimed at CAF reprogramming and ECM normalization, arguing that spatially resolved targeting of the stroma represents a tractable path to overcoming resistance in these refractory cancers.