Abscopal effect in melanoma: effective treatment in situ may unlock systemic antitumor immunity

The abscopal effect—where localized treatment, typically radiotherapy, triggers regression of distant metastatic tumors—remains a rare yet clinically impactful phenomenon in solid tumor oncology. First reported in 1953 and later linked to immune-mediated mechanisms, its relevance has surged with the rise in immunotherapies, especially immune checkpoint inhibitors. Melanoma, due to its high immunogenicity and mutational load, shows the greatest incidence of abscopal responses. Though historically uncommon, these responses are increasingly observed with combination therapies and intralesional agents. Clinical translation, however, is hindered by inconsistent outcomes, absence of predictive biomarkers, and suboptimal treatment protocols. Mechanistically, the effect involves immunogenic cell death, antigen release, T-cell activation, and contributions from the nervous system. This review consolidates current insights into the abscopal effect in melanoma, emphasizing its neuroimmunological underpinnings, clinical evidence, and therapeutic promise. We explore the dynamic between local and systemic immune responses, tumor immunogenicity, and emerging strategies such as neural modulation and combinatorial approaches. Despite existing barriers, the abscopal effect offers a compelling framework for transforming tumors into in situ vaccines, potentially redefining metastatic cancer therapy. Long-term data and our findings suggest that effective in situ treatment—whether targeting primary or metastatic lesions—may be pivotal in achieving cancer eradication.