Tumour-Derived Extracellular Vesicles in Chemotherapy Resistance: Molecular Pathways, Clinical Implications and Therapeutic Opportunities

Chemotherapy remains a central strategy in cancer treatment; however, its effectiveness is often diminished by the emergence of drug resistance, which contributes to over 90% of cancer-related deaths. Traditionally, resistance has been linked to genetic mutations and altered drug metabolism. Recent findings, however, highlight the critical role of extracellular vesicles (EVs) in mediating intercellular communication and facilitating adaptive resistance.

This review examines the involvement of tumour-derived EVs in chemotherapy resistance, focusing on their cargo microRNAs (miRNAs), proteins, and lipids and their impact on drug efflux, apoptosis evasion, and immune suppression.

EVs facilitate resistance through various mechanisms. For instance, EVs transfer ATP-binding cassette (ABC) transporters such as P-glycoprotein, enhancing drug efflux and promoting multidrug resistance. Oncogenic miRNAs (e.g., miR-21, miR-155) within EVs suppress pro-apoptotic genes (PTEN, CASP3), impeding cell death. Moreover, EVs contribute to tumour microenvironment remodelling by activating cancer-associated fibroblasts and carrying PDL1 to suppress T-cell responses.

EV-derived biomarkers including circulating miRNAs (miR-192, miR-484, miR-205) and DNA mutations (KRAS, TP53, EGFR) offer potential for non-invasive monitoring. Therapeutic strategies such as EV inhibition (e.g., GW4869, Rab27a inhibitors) and engineered EVs for targeted delivery are promising.

EV-targeted approaches may transform personalised cancer therapy. Nonetheless, overcoming challenges related to EV heterogeneity, standardisation, and specificity is essential for clinical translation. Future work should prioritise tumour-selective EV inhibition and AI-based biomarker discovery.