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“However, DHHC3 does control primary melanoma growth by supporting anti-melanoma immunity.”

BUFFALO, NY – June 17, 2026 – A new research paper was published in Volume 17 of Oncotarget on June 8, 2026, titled “DHHC3 interferes with antitumor immunity in melanoma cells.”

The study was led by first author and corresponding author Chandan Sharma and corresponding author Martin E. Hemler from the Department of Cancer Immunology and Virology at the Dana-Farber Cancer Institute.

Melanoma is one of the most aggressive forms of skin cancer and is highly influenced by interactions between tumor cells and the immune system. Although modern immunotherapies have transformed treatment for many patients, researchers continue to search for molecular mechanisms that enable tumors to evade immune attack and continue growing.

In this study, researchers investigated DHHC3, a protein acyltransferase that regulates protein palmitoylation and helps maintain cellular redox balance. Previous studies had linked elevated DHHC3 expression to poor outcomes in several cancers, but its role in melanoma and anti-tumor immunity remained unclear.

To explore this question, the team used CRISPR gene editing to eliminate DHHC3 expression in B16F10 melanoma cells. Loss of DHHC3 caused a marked increase in oxidative stress and cellular senescence, as demonstrated by elevated TXNIP expression, increased reactive oxygen species levels, and enhanced expression of senescence-associated markers.

The effects became even more striking when the cells were studied in animal models. Melanoma cells lacking DHHC3 formed significantly smaller tumors in immunocompetent mice. In contrast, tumor growth was not significantly reduced in immunodeficient mice lacking functional immune responses. These findings suggest that the anti-tumor effect of DHHC3 loss depends largely on activation of the immune system rather than direct impairment of tumor cell growth.

Further analyses revealed major changes in the tumor immune microenvironment. DHHC3-deficient tumors contained substantially higher numbers of natural killer (NK) cells, M1 macrophages, CD4-positive T cells, and CD8-positive T cells, all of which play important roles in anti-cancer immunity. At the same time, populations of pro-tumor immune cells, including M2 macrophages and myeloid-derived suppressor cells (MDSCs), were reduced.

Interestingly, despite the profound effects on primary tumor growth, DHHC3 loss did not significantly reduce metastatic spread to the lungs in either immunocompetent or immunodeficient mice. The investigators also observed no meaningful differences in melanoma cell proliferation under standard laboratory culture conditions, indicating that DHHC3 primarily influences tumor growth through immune-related mechanisms rather than intrinsic growth regulation.

The researchers propose that increased oxidative stress and senescence following DHHC3 ablation may trigger a senescence-associated secretory phenotype (SASP), leading to recruitment of anti-tumor immune cells that help suppress melanoma growth.

“Together these results provide firm evidence for DHHC3 having an immunoregulatory role and further support the potential of DHHC3 as a target for anti-cancer therapy in melanoma.”

According to the authors, the findings reveal an important immunoregulatory function for DHHC3 in melanoma. By helping tumors avoid immune surveillance, DHHC3 may contribute to melanoma progression. Targeting DHHC3 could therefore represent a novel strategy for enhancing anti-tumor immunity and improving responses to cancer therapy.

Overall, the study demonstrates that DHHC3 supports melanoma growth primarily by limiting anti-tumor immune responses rather than by directly promoting tumor cell proliferation. These findings provide new insight into the relationship between oxidative stress, cellular senescence, and cancer immunity, while identifying DHHC3 as a promising therapeutic target for future melanoma treatment strategies.

DOI: https://doi.org/10.18632/oncotarget.28880         

Correspondence to: Martin E. Hemler – [email protected], Chandan Sharma – [email protected]     

Keywords: cancer, oxidative stress, DHHC3, anti-cancer immunity, palmitoylation, melanoma

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