Transposable elements and homotypic niches drive immune dynamics and resistance in melanoma epigenetic-based immunotherapy.

Authors

Erika Ciervo, Francesco Ceccarelli, Anna Maria Di Giacomo, Piera Grisolia, Alessia Covre, Zein Mersini Besharat, Antonio De Falco, Francesca Pia Caruso, Luigi Laezza, Luigi Ferraro, Gloria Mas Martin, Daniel Bilbao, Sion Williams, Benjamin Currall, Maria Fortunata Lofiego, Tommaso Sani, Elisabetta Ferretti, Yan Guo, Sean B Holden, Ines Simeone, Roberta Mortarini, Andrea Anichini, Michele Maio, Teresa Maria Rosaria Noviello, Michele Ceccarelli

Published in

Science advances. Volume 12. Issue 32. Pages eaed1318. Aug 07, 2026. Epub Aug 07, 2026.

Abstract

Melanoma plasticity drives immune evasion and therapy resistance through dynamic cell-state transitions beyond genetic alterations. Although epigenetic remodeling is central to this process, its impact under therapeutic pressure remains unclear. We profiled longitudinal biopsies from patients with melanoma treated in the phase 1b NIBIT-M4 epi-immunotherapy trial [NCT02608437, DNA (cytosine-5)-methyltransferase 1 inhibitor plus anti-CTLA-4] using single-cell multiome and spatial transcriptomics. Seven malignant meta-programs were identified, including a rare Wnt/β-Catenin melanocytic state and a dedifferentiated neural crest-like state enriched in nonresponders. Spatial analyses showed that homotypic clustering stabilizes resistant programs, with neural crest-like cells forming compact niches. Responders displayed enrichment of antigen presentation/interferon program and coordinated T and B cell expansion, whereas nonresponders retained stable neural crest-like clusters. Epigenetic therapy reactivated transposable elements, priming innate immunity and enhancing immunogenicity. Nuclear factor of activated T cells, cytoplasmic 2 (NFATC2) emerged as a master regulator of neural crest-like states and resistance; its perturbation promoted differentiation and immunogenicity. These findings define mechanisms of resistance and nominate β-Catenin and NFATC2 as therapeutic vulnerabilities.

PMID:
42566510
Bibliographic data and abstract were imported from PubMed on 08 Aug 2026.

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