Tumor microenvironment-driven therapeutic resistance in pancreatic ductal adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most treatment-refractory malignancies, with limited and often transient benefit from chemotherapy, targeted therapy, immunotherapy, and radiotherapy. Therapeutic resistance is increasingly recognized as an ecosystem-level process arising from reciprocal interactions between malignant cells and the tumor microenvironment (TME). Dense extracellular matrix, cancer-associated fibroblasts (CAFs), pancreatic stellate cells (PSCs), dysfunctional vasculature, immunosuppressive myeloid and lymphoid populations, hypoxic niches, metabolic networks, microbiota, extracellular vesicles (EVs), and neural components collectively restrict drug delivery and promote adaptive survival, immune escape, stemness, and treatment-induced evolution. This review integrates these processes into a PDAC resistance ecosystem framework. We discuss how stromal remodeling, hypoxia-driven adaptation, metabolic-immune crosstalk, extracellular communication, cancer stem cell plasticity, and TME-regulated autophagy and ferroptosis contribute to resistance across therapeutic modalities. We further evaluate emerging strategies involving stromal reprogramming, myeloid and immune remodeling, metabolic intervention, hypoxia targeting, and regulated cell-death sensitization. Particular emphasis is placed on the limited clinical translation of indiscriminate stromal depletion and single-target approaches. Finally, we propose that spatial multi-omics, longitudinal biomarker profiling, and adaptive combination therapy will be required to identify dominant resistance programs and guide patient-specific intervention in PDAC.