For decades, treating melanoma that has spread through lymphatic channels near the primary tumor—so-called in-transit disease—focused on shrinking visible lesions. A growing body of clinical evidence now suggests the real prize is not local tumor clearance but triggering durable systemic immunity, fundamentally reframing what these treatments are supposed to accomplish.
This review, published in Current Oncology, synthesizes clinical trial data across multiple intralesional platforms to identify which mechanisms actually drive meaningful outcomes. The analysis distinguishes agents capable of inducing immunogenic cell death—a form of tumor destruction that alerts and activates the immune system—from those that merely stimulate pattern-recognition receptors without sustaining antigen presentation. Oncolytic viral platforms, specifically talimogene laherparepvec (T-VEC) and the next-generation vusolimogene oderparepvec (RP1), along with plasmid interleukin-12 delivered via electroporation (Tavo-EP), demonstrate the strongest signals, particularly when combined with checkpoint inhibitors such as anti-PD-1 agents. In contrast, therapies relying solely on innate immune pathway activation have produced inconsistent results in randomized settings. The review also highlights focused ultrasound as an emerging noninvasive modality for remodeling the immunosuppressive tumor microenvironment prior to or alongside immunotherapy.
This mechanistic framework matters because it moves treatment selection away from empirical sequencing toward biology-driven rationale. In the broader immunotherapy landscape, the concept of converting 'cold' tumors into immunologically 'hot' ones has gained substantial traction, and intralesional delivery offers a spatially precise way to accomplish this without the systemic toxicity of high-dose cytokines. The key limitation here is that this is a narrative review rather than a meta-analysis, so effect-size comparisons across trials must be interpreted cautiously given heterogeneous patient populations, staging criteria, and combination regimens. Still, the synthesis is clinically valuable and aligns with Phase II data supporting RP1 plus nivolumab combinations. The incremental but coherent conclusion—that locoregional therapies should be selected to overcome immune resistance, not merely debulk disease—represents a meaningful conceptual advance for oncology practitioners managing this challenging presentation.