HypoxamiRs in pancreatic cancer: master regulators of the hypoxic tumor microenvironment

Pancreatic cancer (PC) is characterized by aggressive progression, chemoresistance, and immune evasion, largely driven by its hypoxic tumor microenvironment (TME). The extensive desmoplastic reaction in PC, characterized by dense stromal fibrosis, exacerbates hypoxia by impairing blood flow, creating a hostile environment that limits therapeutic efficacy. Hypoxia-induced microRNAs (HypoxamiRs) have emerged as critical regulators of these processes, modulating cellular pathways that promote tumor survival and therapy resistance. HypoxamiRs exert their effects by interacting with hypoxia-inducible factors, including HIF-1α and HIF-2α. Beyond their direct impact on tumor cells, HypoxamiRs modulate the behavior of immune and stromal cells within the hypoxic TME. Key contributors to hypoxia, such as cancer-associated fibroblasts, pancreatic stellate cells, macrophages, and natural killer (NK) cells, facilitate HypoxamiR transfer via exosomes. This review explores the multifaceted roles of HypoxamiRs in key processes such as immune modulation, chemoresistance, epithelial-mesenchymal transition (EMT), autophagy, angiogenesis, and apoptosis in pancreatic cancer. We also highlight the complex interplay between HypoxamiRs and other non-coding RNAs (ncRNAs) in regulating hypoxia-driven pathways. Investigating these complex interactions provides critical insights for developing novel therapeutic strategies to overcome chemoresistance and immune evasion in pancreatic cancer.