The Evolving Role of Intralesional Therapy in In-Transit Melanoma.

In-transit melanoma represents a biologically aggressive form of locoregional disease in which effective management requires integration of local tumor control with systemic immune engagement. Although traditional regional therapies achieve high response rates, they have not consistently translated into durable systemic survival. This review evaluates the clinical development and mechanistic rationale of intralesional therapies, including cytokine-based approaches, oncolytic viruses, immunocytokines, and energy-based delivery platforms, as immunologic intermediaries. Analysis of clinical trial data suggests that outcomes may heavily depend on an agent's ability to induce immunogenic cell death and sustain antigen presentation. Platforms such as talimogene laherparepvec (T-VEC), vusolimogene oderparepvec (RP1), and tavokinogene telseplasmid with electroporation (Tavo-EP) demonstrate enhanced activity in combination with checkpoint blockade, whereas therapies limited to pattern-recognition receptor activation have shown inconsistent efficacy in randomized trials. Emerging noninvasive technologies, such as focused ultrasound, may further expand strategies for remodeling the immunosuppressive tumor microenvironment to enable immune sensitization. These findings support a shift toward mechanism-based treatment selection in which locoregional therapies function to overcome immune resistance rather than solely reduce tumor burden.