Overcoming melanoma drug resistance: Mechanisms and clinical progress of oncolytic viruses combined with immune checkpoint inhibitors (Review)

Abstract

Although immune checkpoint inhibitors (ICIs) have revolutionized the management of advanced melanoma, a major clinical challenge persists: Nearly 50% of patients develop primary or acquired resistance and therefore derive no meaningful clinical benefit. As ICIs are increasingly used in earlier disease settings, including adjuvant and neoadjuvant therapy, the population of patients with ICI-resistant disease continues to grow. For patients whose disease progresses after first-line combined programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) blockade, effective salvage options remain limited, highlighting an urgent unmet medical need. Oncolytic viruses (OVs), which exert antitumor effects through the dual mechanisms of selective tumor cell lysis and immunomodulatory remodeling of the tumor microenvironment, represent a compelling therapeutic strategy for overcoming ICI resistance. Recent clinical and preclinical advances have moved OV–ICI combination regimens from conceptual strategies to clinically evaluable interventions for refractory melanoma. Nevertheless, several translational barriers impede their broader implementation, including interpatient heterogeneity in treatment response, uncertainty regarding the optimal sequencing and dosing of combination therapies, and the lack of validated predictive biomarkers. The present review systematically synthesizes emerging clinical evidence and mechanistic insights into OV–ICI synergy to inform rational trial design, refine combination strategies, and accelerate the development of precision immuno-oncology approaches.