A multidimensional landscape of extracellular vesicle-mediated tumor drug resistance: mechanisms, biomarkers, engineered drug delivery, and clinical translation

Tumor drug resistance is a major clinical challenge that limits the efficacy of chemotherapy, targeted therapy, and immunotherapy, thereby contributing to tumor recurrence, metastasis, and reduced overall patient survival rates. Recent studies reveal that extracellular vesicles (EVs) in the tumor microenvironment act as key mediators of intercellular communication. They play a central role in mediating tumor cell resistance by transporting functional cargo, including RNA, proteins, and lipids. This review outlines the mechanisms of EV-mediated tumor resistance, including key processes such as drug efflux, evasion of apoptosis, maintenance of epithelial-mesenchymal transition and cancer stem cell phenotypes, remodeling of the immune microenvironment, metabolic reprogramming, and expansion of resistant cell populations. It also discusses the use of EVs as biomarkers of resistance and their associated detection technologies. Furthermore, this paper highlights therapeutic strategies for reversing drug resistance through engineered EVs, including the delivery of small molecules, nucleic acid therapeutics, and key bioactive components. It also reviews current preclinical studies and progress toward clinical translation of EV-based resistance reversal strategies. This review aims to elucidate the role and translational potential of EVs in tumor drug resistance through a systematic approach that integrates mechanism exploration, biomarker identification, engineered drug delivery, and clinical translation. It provides a comprehensive reference to facilitate further advances in this field, from basic research to clinical practice.