Researchers at NYU Langone Health and its Perlmutter Cancer Center have identified a molecule that simultaneously fuels the growth of melanoma and helps tumors evade the immune system.

The study, published in Cancer Discovery, highlights the transcription factor HOXD13 as a primary driver of skin cancer progression. According to the research, the team compared transcription factor (TF) expression across early-stage melanoma, benign skin lesions, and other cancers, and found HOXD13 to be upregulated across primary to metastatic melanoma, irrespective of the oncogenic driver. HOXD13 was found to act as a genetic switch that triggers several harmful pathways, includig angiogenesis, immune shielding – increasing levels of a protein called CD73, which produces adenosine and prevents tumor infiltration by T cells. HOXD13 also reduced T cell activity in patients with high HOXD13 activity.

The project was supported by a slew of grants from the National Institutes of Health (grants P30CA016087, R01CA274100, P50CA225450, and U54CA263001), with additional support from the Melanoma Research Foundation, the Melanoma Research Alliance, United Kingdom Medical Research Council, Brazilian National Council for Scientific and Technological Development (CNPQ), and the Wellcome Trust.

Implications for treatment

HOXD13 is a sequence-specific homeobox transcription factor in the HOXD cluster that helps encode positional identity during embryonic development, especially distal limb/digit patterning. The study suggests that suppressing HOXD13 or its downstream pathways could be a highly effective treatment strategy. In mouse models, researchers were able to reverse HOXD13-induced tumor growth and enable T cell infiltration through combined VEGFR and adenosine receptor (AdR) inhibition, revealing a dual pro-angiogenic and immunosuppressive HOXD13 axis with therapeutic relevance.

Notably, transcription factors are classically difficult to drug with small molecules. Instead, gene/RNA-directed (siRNA, ASO, CRISPR/Cas-based RNA targeting) or targeted protein degradation approaches may offer greater promise of directly targeting HOXD13.