The Role of Tumor-Intrinsic HuR in Modeling the Pancreatic Tumor Microenvironment: Molecular Mechanisms and Therapeutic Opportunities

Pancreatic ductal adenocarcinoma (PDAC) remains largely refractory to therapy, due in part to the complex interplay between tumor cells and their microenvironment. Human antigen R (HuR/ELAVL1), a ubiquitously expressed RNA-binding protein, is emerging as an important regulator both of tumor-intrinsic and tumor-extrinsic pathways that govern PDAC progression. While the role of HuR in promoting cancer cell survival under stress is well established, recent studies reveal its broader role in shaping the tumor microenvironment (TME), including metabolic rewiring, stromal activation, angiogenesis, and immune modulation. In this review, we examine how tumor-intrinsic HuR drives epithelial-mesenchymal transition, stabilizes key transcripts involved in metabolic adaptation, and alters the tumor secretome to influence extracellular matrix deposition and fibroblast behavior. We further explore the role of HuR in regulating immune cell function and the immune landscape of PDAC. Notably, HuR-driven TME remodeling reinforces environmental stressors that further activate HuR, establishing a feed-forward loop that drives disease progression. These findings underscore HuR as a central regulator of the PDAC TME and therapeutic resistance, and thus, highlight its potential as a target in PDAC.