Unraveling exosome-mediated cancer therapy resistance: pathways and therapeutic challenges

Extracellular vesicles (EVs) have emerged as key cell-to-cell communication mediators and play significant roles in both physiological and pathological processes. In EVs, exosomes represent a distinct subpopulation of EVs that have been found to be involved in cancer initiation and therapeutic resistance. Exosomes transfer a diverse spectrum of molecular cargos that have significant effects on the tumor microenvironment (TME), thereby enabling cancer initiation, metastasis, and therapeutic resistance. Exosomes have recently been of interest in cancer therapy due to their role as important mediators of treatment resistance. The exosomal molecular content-proteins, miRNAs, and lncRNAs-allows exosomes to perform functions including drug efflux and detoxification, cell death pathway modulation, induction of epithelial-to-mesenchymal transition (EMT), and suppression of the immune system. In addition to facilitating immune and stromal cell interactions, exosomes cause extracellular matrix remodeling and induce tumor heterogeneity, making it more difficult to respond to therapy. This review covers intricate roles of exosomes in cancer therapy resistance with regard to their biogenesis, molecular content, and functional impact in the TME. Along with this, we also discuss new therapeutic strategies to overcome exosome-mediated resistance including utilizing exosome inhibitors, designed exosome therapy, and combination with conventional therapies. While exosomes hold promise in prediction and diagnosis through their biomarker function, their heterogeneous origins and cryptic functions make it difficult to target interventions. This review emphasizes that research on exosome-mediated pathways is urgently required to develop new therapeutic strategies that can improve cancer treatment outcomes.