DNMT1 is associated with anti-PD-1 resistance and regulates the STAT3/PD-L1-CD8⁺ T-cell axis in melanoma.

Authors

Yujia Sun, Chen Chen, Yingjie Wang, Chuanxin Cui

Published in

Biochemical pharmacology. Pages 118392. Aug 23, 2026. Epub Aug 23, 2026.

Abstract

Transcriptomic analysis of melanoma (MM) patients receiving anti-programmed cell death protein 1 (anti-PD-1) blockade identified differentially expressed genes and co-expression modules associated with therapeutic response. Integrated transcriptomic and proteomic analyses, together with least absolute shrinkage and selection operator (LASSO) regression, identified deoxyribonucleic acid (DNA) methyltransferase 1 (DNMT1) as a key resistance-associated factor. Functional enrichment suggested that DNMT1 was involved in DNA methylation, immune activation, and extracellular matrix remodeling. Further immune infiltration and single-cell analyses showed that high DNMT1 expression was associated with reduced cluster of differentiation 8-positive (CD8⁺) T-cell infiltration and an immunosuppressive tumor microenvironment. Mechanistically, DNMT1 was linked to signal transducer and activator of transcription 3 (STAT3) activation and programmed death-ligand 1 (PD-L1) upregulation. In MM cell models, DNMT1 knockdown reduced STAT3/PD-L1 signaling and enhanced CD8⁺ T-cell cytotoxic activity, as reflected by increased interferon gamma (IFN-γ) and Granzyme B production. Both genetic DNMT1 knockdown and pharmacological DNMT1 inhibition enhanced CD8⁺ T-cell-mediated antitumor activity in MM-CD8⁺ T-cell co-culture systems, and nivolumab further strengthened these effects under in vitro conditions. These findings identify DNMT1 as a resistance-associated epigenetic regulator and suggest that DNMT1 may participate in anti-PD-1 resistance through the STAT3/PD-L1-CD8⁺ T-cell axis. Further in vivo studies are required to validate whether DNMT1 inhibition can enhance the therapeutic efficacy of anti-PD-1 therapy in MM.

PMID:
42633802
Bibliographic data and abstract were imported from PubMed on 24 Aug 2026.

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