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Peer-reviewedCC BY 4.0Frontiers in Immunology

Towards epigenetically informed and biobank-driven precision immunotherapy in melanoma

  • Ludovica Ciuffreda1
  • Italia Falcone1
  • Cristina Sorino1
  • Alessandro Valenti2
  • Celeste Accetta3
  • Francesca De Nicola1
  • Valentina Roglia4
  • Maurizio Fanciulli1
  • Giovanni Blandino5
  • Edoardo Pescarmona3
  • Simona Di Martino3
5 affiliations
  1. 1Gene expression and Cancer Model Unit, Department of Research, Advanced Diagnostics and Technological Innovation, Translational Research Area, IRCCS Regina Elena National Cancer Institute
  2. 2Radiology and Diagnostic Imaging Unit, Department of Clinical and Dermatological Research, San Gallicano Dermatological Institute IRCCS
  3. 3Department of Pathology Unit, Tissue Biobank, IRCCS Regina Elena National Cancer Institute
  4. 4Gynecologic Oncology Unit, Department of Experimental Clinical Oncology, IRCCS Regina Elena National Cancer Institute
  5. 5Scientific Direction, IRCCS Regina Elena National Cancer Institute
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Abstract

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.

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Cite

BibTeXRIS
BibTeX
@article{ciuffreda2026towards,
  title = {{Towards epigenetically informed and biobank-driven precision immunotherapy in melanoma}},
  author = {Ludovica Ciuffreda and Italia Falcone and Cristina Sorino and Alessandro Valenti and Celeste Accetta and Francesca De Nicola and Valentina Roglia and Maurizio Fanciulli and Giovanni Blandino and Edoardo Pescarmona and Simona Di Martino},
  journal = {Frontiers in Immunology},
  year = {2026},
  month = oct,
  doi = {10.3389/fimmu.2026.1932718},
  url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1932718/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Towards epigenetically informed and biobank-driven precision immunotherapy in melanoma
AU  - Ludovica Ciuffreda
AU  - Italia Falcone
AU  - Cristina Sorino
AU  - Alessandro Valenti
AU  - Celeste Accetta
AU  - Francesca De Nicola
AU  - Valentina Roglia
AU  - Maurizio Fanciulli
AU  - Giovanni Blandino
AU  - Edoardo Pescarmona
AU  - Simona Di Martino
PY  - 2026
DA  - 2026/10/06
JO  - Frontiers in Immunology
DO  - 10.3389/fimmu.2026.1932718
UR  - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1932718/full
AB  - 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.
SN  - 1664-3224
ER  -