RNA-based cancer immunotherapy: Harnessing the power of RNA nanoparticles for melanoma treatment.

RNA-based cancer immunotherapy has emerged as a next-generation strategy in oncology, harnessing the versatile properties of RNA molecules to activate and modulate antitumor immunity. In melanoma, a highly immunogenic yet evasive malignancy, RNA therapeutics offer promising avenues for overcoming immune resistance, tumor heterogeneity, and treatment failure. Messenger RNA (mRNA) vaccines have led the field, encoding tumor-associated antigens or neoantigens to prime dendritic cells and elicit cytotoxic T cell responses. Meanwhile, small interfering RNAs (siRNAs) and microRNAs (miRNAs) are being deployed to silence immunosuppressive pathways, reprogram tumor cells, and modulate the tumor microenvironment. More recently, circular RNAs (circRNAs), PIWI-interacting RNAs (piRNAs), and self-amplifying RNAs (saRNAs) have expanded the immunological landscape by targeting regulatory feedback loops, enhancing checkpoint inhibition, and amplifying immune activation at multiple levels. This review synthesizes mechanistic, preclinical, and clinical evidence on RNA-based cancer immunotherapy in melanoma, with a focus on the role of RNA nanoparticles. We highlight recent advances, contradictions, and delivery innovations, explore the interplay between RNA and melanoma cell plasticity, and identify opportunities for future clinical application. With the developments in RNA technologies, integrating artificial intelligence, synthetic biology, and organ-targeted delivery will be central to establishing fully personalized and adaptive immunotherapy platforms. The future of melanoma therapy in our hands will depend on encoding RNA and engineering it in a way to outsmart the tumor's elegance and rewire the immune response.