Loss of TET2 sulfhydration results in destabilization of TET2 and down-regulation of the immune response in melanoma.

Loss of TET2 protein leads to reduced DNA 5-hydroxymethylation (5-hmC), a key epigenetic alteration in melanoma, yet the regulatory mechanism governing TET2 stability remains unclear. Here, TET2 sulfhydration was analyzed in clinical melanoma samples, with sulfhydration sites identified by mass spectrometry, and the effects of active sulfur on TET2 stability, catalytic activity, and global 5-hmC assessed in melanoma cells. TET2 sulfhydration was significantly depleted in melanoma and further reduced in advanced stages. The cysteine-rich zinc finger domain at C1186/1202 was identified as the key sulfhydration site, which is essential for maintaining TET2 stability and enzymatic activity. Active sulfur restored TET2 sulfhydration, up-regulated TET2 protein, and reprogrammed global DNA hydroxymethylation. Notably, active sulfur synergized with anti-PD-1 therapy by enhancing IFN-γ-induced Th1-type chemokine and MHC-I expression in melanoma cells, thereby boosting CD8+ T-cell-mediated immune responses. These findings demonstrate that TET2 sulfhydration at C1186/1202 is a crucial post-translational modification for TET2 stability and function, playing a key role in epigenetic regulation and antitumor immunity, and highlight the immunoadjuvant potential of reactive sulfur species in melanoma immunotherapy.