Circulating EV-microRNAs Are Dynamic Biomarkers of Resistance to Therapeutic Immunomodulation in Metastatic Melanoma

BACKGROUND:Melanoma is the most aggressive skin cancer, with a 50% five-year mortality in metastatic or unresectable cases. Non-invasive biomarkers are crucial for guiding treatment. MicroRNAs (miRNAs), especially those encapsulated in extracellular vesicles (EVs), are stable in plasma and hold promise as biomarkers. METHODS:This study analyzed EV-associated miRNAs (EV-miRNAs) from 50 blood samples of 18 stage III-IV melanoma patients treated with anti-CTLA-4 immunotherapy and a DNA hypomethylating agent. Samples were collected at baseline, week 4, and week 12. Patients were classified as responders (R) or non-responders (NR). RESULTS:A baseline signature of four EV-miRNAs predicted primary resistance. Treatment altered 15 EV-miRNAs at week 4 and 51 at week 12; nine were consistently modulated. At week 12, 27 EV-miRNAs differed between NR and R, with miR-1203 and miR-566-3p up-regulated in NR, linked to resistance and poor survival. CONCLUSIONS:These results highlight EV-miRNAs as non-invasive biomarkers for predicting and monitoring therapy response.