When a tumor grows, it forms a supportive structure called the tumor stroma, which contains blood and lymphatic vessels for nourishment and oxygen. The growth of lymphatic vessels (lymphangiogenesis) often leads to a poor outcome because it helps cancer spread to other organs.
Researchers at the University of Geneva found that an enzyme in these vessels supports immune cells during anti-tumor treatments. This discovery could improve immunotherapy treatments.
Though blocking lymphangiogenesis seemed like a good way to prevent cancer from spreading, it didn’t work well. The lymphatic vessels also help transport and activate immune cells to fight the tumor, and their role is more complex than previously thought.
The team aims to understand how these vessels respond to tumors to enhance the immune response against cancer.
Researchers studied the gene expression of lymphatic endothelial cells in melanoma (a type of skin cancer) and healthy mouse skin. They found that an enzyme called CH25H was over-expressed in the lymphatic vessels of tumors, which was confirmed in humans.
The more lymphatic vessels in the melanoma, the more this enzyme was over-expressed. Patients with high levels of CH25H had better outcomes, especially those treated with immune checkpoint inhibitors, a type of immunotherapy.
CH25H converts cholesterol into a metabolite called 25-hydroxycholesterol, which plays a role in antiviral immunity. This enzyme helps the immune system in melanoma by counteracting the tumor’s defense mechanisms.
The tumor microenvironment usually produces factors that inhibit immune cell activation, but 25-hydroxycholesterol prevents this inhibition, allowing for better activation of anti-tumor immunity.
The team deleted the CH25H enzyme in mouse lymphatic endothelial cells, which significantly dropped 25-hydroxycholesterol levels in melanoma tumors. This resulted in weaker immune activity and a less effective fight against the disease.
In contrast, mice vaccinated with tumor antigens showed a clear increase in CH25H enzyme expression and 25-hydroxycholesterol production, leading to better immune cell activation. This matches clinical observations: in patients undergoing immunotherapy, the level of this enzyme indicates how well the treatment works.
Prof. Hugues suggests their discovery could help predict immunotherapy success and tailor treatments to each patient.
Lymphatic vessels have traditionally been seen as simple transport routes. However, their work shows these vessels play a much more complex role. They adapt to the tumor microenvironment and immune system changes.
The stroma (support structure) is not just a scaffold for the tumor but a complex microworld with both helpful and harmful roles. Therefore, instead of targeting all lymphangiogenesis, focusing on specific functions to fight the disease more effectively is better.
Journal Reference:
- Sun, M., Garnier, L., Chevalier, R. et al. Lymphatic-derived oxysterols promote anti-tumor immunity and response to immunotherapy in melanoma. Nat Commun 16, 1217 (2025). DOI: 10.1038/s41467-025-55969-w
Source: Tech Explorist
