DHHC3 interferes with antitumor immunity in melanoma cells

Chandan Sharma1, Soonyean Hwang2, Qingshi Liu3 and Martin E. Hemler1 1 Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA 2 Current address: UCB, 87 Cambridge Park Dr, Cambridge, MA 02140, USA 3 Current address: Chinese Institutes for Medical Research, Beijing 100069, China Correspondence to: Martin E. Hemler, email:martin_hemler@dfci.harvard.edu Chandan Sharma, email:csharma@mgh.harvard.edu Keywords: oxidative stress; DHHC3; anti-cancer immunity; palmitoylation; melanoma Received: August 18, 2025     Accepted: April 30, 2026     Published: June 08, 2026 Copyright: © 2026 Sharma et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT The protein-acyltransferase DHHC3 supports a few different tumor malignancies, but mechanisms have been unclear. Here we report that DHHC3-null B16F10 melanoma cells showed markedly elevated oxidative stress and senescence, accompanied by diminished tumor growth within immunocompetent C57/BL6 mice, but not in immunodeficient NOD-SCID mice. These results suggest that absence of DHHC3 enhances innate and/or adaptive anti-melanoma immunity. Consistent with this, DHHC3-null melanomas contained elevated numbers of anti-tumor cells (M1 macrophages, NK, CD4+T, CD8+T), whereas pro-tumor cells (M2 macrophages, MDSCs) were diminished. Unexpectedly, DHHC3 ablation minimally affected experimental metastasis of cells injected into either immunocompetent C57/BL6 or immunodeficient NOD-SCID mice. We conclude that DHHC3 ablation does not fundamentally alter melanoma cell growth and invasion/metastasis (independent of the immune system) despite its effects on oxidative stress and senescence. However, DHHC3 does control primary melanoma growth by supporting anti-melanoma immunity.