Opportunities, challenges, and future perspectives of oncolytic virus therapy for malignant melanoma.

Malignant melanoma is characterized by high heterogeneity, aggressive metastatic potential, and a profoundly immunosuppressive "cold" tumor microenvironment, contributing to broad therapeutic resistance and suboptimal responses to immunotherapy. Conventional PD-1 inhibitors yield an ORR of only 38%. As an emerging class of immunotherapeutic agents, oncolytic viruses (OV) induce ICD, promoting the release of DAMPs and activating innate immune pathways such as cGAS-STING, thereby transforming "cold" tumors into "hot" phenotypes and eliciting robust anti-tumor responses. Mechanistically, OV therapy increases the proportion of CD103+ dendritic cells (DCs) in lymph nodes from 5% to 25% and enhances DC-tumor synapse formation by 300%, facilitating efficient cross-presentation of tumor antigens and T-cell priming. Clinically, T-VEC combined with pembrolizumab achieves a 48.6% ORR with grade ≥3 AEs occurring in <20% of patients-superior to either monotherapy or conventional chemoradiotherapy. Nonetheless, OV therapy faces challenges including tumor heterogeneity, core mechanistic limitations, viral shedding risks, and regulatory hurdles. Over the next 5-10 years, single-cell RNA sequencing is expected to unravel molecular heterogeneity in melanoma, while CRISPR/Cas systems may enable the design of tailored OV to overcome resistance. Additional strategies such as serotype switching, JAK/STAT inhibition, and arming OV with hyaluronidase or STING agonists are under investigation to overcome immune and stromal barriers. Integration of artificial intelligence with biomarkers-such as neutralizing antibody titers, ISG expression, and STING methylation-may further enable personalized OV-based therapies. This review discusses OV therapy's mechanisms, clinical impact, and future prospects in melanoma treatment.