20 Feb Melanoma: NYU Study Outlines Mechanisms Tumors Use to Sustain Blood Supply and Escape Immune Detection
Dr. Berico
MedicalResearch.com Interview with:
Pietro Berico, M.Sc., Ph.D.
Postdoctoral research fellow
Hernando Lab
NYU Grossman School of Medicine
NYU Langone Health
New York, NY 1001
MedicalResearch.com: What is the background for this study?
Response: “Cutaneous melanoma arises under chronic UV irradiation, which selects for aggressive malignant clones. Paradoxically, its high mutational burden also promotes neoantigen formation and robust immune activation. Consequently, melanoma must establish immune evasion mechanisms from the earliest stages of tumor development. The lack of specific genetic mutational patterns linked to immune escape points toward non-mutational mechanisms, such as epigenetic reprogramming.
MedicalResearch.com: What are the main findings?
Response: By profiling the expression of thousands of transcription factors (TFs) in naevi and early primary melanoma lesions, we identified HOXD13 as the only TF consistently upregulated candidate associated with immune-cold tumors. We went on to demonstrate that HOXD13 orchestrates a gene program that makes melanoma cells evade the immune response and remodel the blood vessels to gain access to nutrients. Notably, HOXD13-high tumors appear particularly sensitive to a novel therapeutic combination of Lenvatinib and Etrumadenant—targeting angiogenesis and adenosine signaling, respectively—both currently under investigation in advanced clinical trials as individual agents with promising activity across multiple cancer types”.
MedicalResearch.com: How does HOXD13 change the microenvironment to make a tumor less susceptible to immune attack? Does elevating HOXD13 influence any non-malignant cells?
Response: “Through multiple functional studies in human and murine models, we demonstrated that HOXD13 changes chromatin conformation and directly activates the expression of SEMA3A and VEGFA (angiogenic factors), as well as CD73 (an adenosine-producing enzyme). Together, these targets remodel the tumor vasculature to restrict intratumoral immune infiltration and promote T-cell exhaustion.
In parallel, we found that HOXD13 suppresses an antigen-presenting melanoma phenotype characterized by low expression of the major histocompatibility complex. This coordinated cell-autonomous and non–cell-autonomous program suppresses anti-tumor immune responses while preserving adequate nutrient and oxygen supply to sustain tumor growth”.
MedicalResearch.com: What should readers take away from your report?
Response: “Despite our efforts to identify common molecular denominators underlying the hallmarks of cancer, the disease continuously reveals remarkable adaptability, evolving intricate mechanisms to overcome physiological and therapeutic barriers. Our study, along with others, illustrates how cancer cells frequently reactivate developmental programs—such as HOXD13, a transcription factor normally restricted to embryonic limb formation—to gain selective advantages. In this context, our work provides an experimental framework that traces a large-scale epigenetic program to two actionable signaling pathways, offering preliminary evidence of potential clinical benefit. Thus, melanomas exhibiting high levels of HOXD13 and its targets VEGFA and CD73 could be more susceptible to combinations of agents which are separately being tested for therapeutic efficacy in other cancer types”.
MedicalResearch.com: What recommendations do you have for future research as a results of this study?
Response: “The need for modern molecular oncology to adopt truly multi-modal strategies that integrate experimental and computational approaches while starting from broad biological principles”.
MedicalResearch.com: Is there anything else you would like to add? Any disclosures?
Response: Nothing else to disclose.
Citation:
Pietro Berico, Amanda Flores Yanke, Fatemeh Vand-Rajabpour, Catherine Do, Irving Simonin Wilmer, Ines Delclaux, Tara Muijlwijk, Robert Stagnitta, Martha Estefania Vázquez-Cruz, Theodore Sakellaropoulos, Matheus Ribeiro. Costa, Annie Cristhine Moraes Sousa-Squiavinato, Michelle Krogsgaard, Ata S. Moshiri, Iman Osman, Jane A. Skok, Patricia A. Possik, Carla Daniela Robles-Espinoza, Amanda W. Lund, Markus Schober, Eva Hernando; A targetable developmental program co-regulates angiogenesis and immune evasion in melanoma. Cancer Discov 2026; https://doi.org/10.1158/2159-8290.CD-24-1853
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Last Updated on February 20, 2026 by Marie Benz MD FAAD
