Towards epigenetically informed and biobank-driven precision immunotherapy in melanoma

Cutaneous melanoma (CM) is a highly immunogenic and therapeutically intricate solid tumor, exemplifying the interactions between tumors and the immune system. Despite the significant enhancement in survival rates for patients with advanced melanoma due to immune checkpoint inhibitors (ICIs), numerous patients either exhibit resistance to these agents or develop immune evasion mechanisms. This underscores the pressing necessity to identify biological determinants of drug responses. A significant body of research indicates that epigenetic alterations, including DNA methylation, histone modifications, and ATP-dependent chromatin remodeling, are essential in modulating melanoma immunogenicity. This encompasses the modulation of antigen presentation, innate immune detection, interferon (IFN) signaling, melanoma plasticity, and the reconfiguration of the immune microenvironment. Furthermore, in contrast to genetic mutations, these mechanisms are reversible, positioning melanoma as a prime example of epigenetically regulated and potentially therapeutically targeted immune resistance. This review examines the novel insight that epigenetic therapies can enhance the immunological activity of "cold" or immune-excluded melanomas, transforming them into inflamed, drug-responsive tumors. This is achievable by restoring antigenicity and reactivating IFN-related pathways, leading to enhanced immune cell infiltration. The paper also addresses the necessity of longitudinal biobanking combined with integrated multi-omics analyses of epigenomics, transcriptomics, proteomics, and spatial profiling to investigate dynamic tumor-immune configurations, support the validation of candidate biomarkers, and explore biologically informed patient stratification. In conclusion, we propose an integrative model connecting epigenetic vulnerability, immune reconfiguration, and biobank-driven systems biology. This model is proposed as a research framework for investigating future biomarker informed immunotherapy strategies in melanoma.