Hypoxia-Driven Extracellular Vesicle Signaling in Lung Cancer Progression, Immune Evasion, and Therapeutic Resistance

Abstract

Tumor hypoxia is a defining feature of solid tumors, including lung cancer, and a major driver of aggressive disease progression, metastasis, and therapeutic resistance. Although hypoxia-induced signaling is well-characterized at the cellular level, emerging evidence highlights extracellular vesicles (EVs) as critical mediators through which hypoxic tumor cells remodel the tumor microenvironment. EVs transfer proteins, nucleic acids, and metabolites between cells, enabling complex intercellular communication. Their diverse cargo can act synergistically to promote cancer progression by modulating multiple signaling pathways in recipient cells. In lung cancer, hypoxia enhances EV biogenesis and promotes the loading of oncogenic cargo. Hypoxia-conditioned EVs subsequently drive key cancer hallmarks, including angiogenesis, epithelial–mesenchymal transition, metabolic reprogramming, immune suppression, and therapeutic resistance. Despite the diversity of EV cargo, these effects converge on major oncogenic pathways, including PI3K–Akt, STAT3, Wnt/β-catenin, and PD-1/PD-L1 signaling. Therefore, targeting hypoxia-driven EV signaling may suppress tumor progression and improve treatment efficacy. Clinically, the hypoxia–EV axis offers diagnostic and therapeutic opportunities. Circulating EVs containing hypoxia-associated tumor signatures may support non-invasive liquid biopsy approaches for early detection, prognosis, and treatment monitoring. Targeting EV biogenesis or transfer may also help overcome resistance to targeted therapy and immunotherapy.