There are many approaches scientists use to attack cancer—from chemotherapy that assaults rapidly dividing cells, to targeted small molecules that inhibit specific tumor-driving proteins, to immunotherapies that enhance the body’s immune response. However, none of these strategies have, until now, focused specifically on leveraging embryonic antigens on the tumor vasculature. In March 2025, researchers introduced a new method that does exactly that: targeting tumor blood vessels with vaccines developed against embryonic-like proteins, such as fibrillin-2 and oncofetal fibronectin. This is not a cell-based therapy like CAR-T; rather, it’s a vascular-targeted immunotherapy aimed to cut off a tumor’s blood supply.
The tumor vasculature is the network of blood vessels supplying nutrients and oxygen to cancer cells. In healthy adults, blood vessels express a specific set of proteins on their lining, distinct from those in tumors. But in cancer, endothelial cells in tumor-associated blood vessels reexpress embryonic self-antigens proteins normally active only during development. Huijbers et al. used transcriptomic comparisons between embryonic mouse vessels (at days E11 and E18) and mature adult vessels, then overlaid these findings on murine tumor endothelial cells (TECs). They isolated several key proteins—like fibrillin-2, Emilin2, Lox, and Serpine1—that are largely absent in mature tissue vessels but abundant in tumor vessels.
Building on this, the researchers developed conjugate vaccines targeting those antigens. In mouse models, vaccination triggered strong, antigen-specific antibody responses that significantly inhibited tumor growth, all while sparing healthy vasculature. This approach thus offers a precise, immunologically-based shutdown of tumor blood supply, akin to targeted anti–angiogenesis but with a novel antigen-specific twist.
From a therapeutic standpoint, this method complements existing cancer treatments. Chemotherapy and radiation broadly attack dividing cells or DNA, often harming normal tissues and causing side effects. Targeted therapies, such as TKIs, hit specific molecules but often provoke resistance over time. Immunotherapies like checkpoint inhibitors boost immune function, but typically act on cancer cells or T-cells, not directly on tumor vessels.
This vaccine approach represents a fourth modality: immunologically targeting tumor blood vessels by exploiting embryonic antigens that are uniquely re-expressed in tumors, leaving healthy vessels unharmed. It offers high specificity and a potentially favorable safety profile: preclinical data so far show effective tumor inhibition without notable vascular toxicity.
However, several challenges remain:These findings are preclinical, based on mouse models; human safety, dosing, and efficacy data are not yet available. Tumor heterogeneity means vascular antigens may vary between cancers, or even within a single patient’s tumor. There’s a minor risk that the immune system could target normal tissues expressing low levels of these antigens, potentially leading to off-target effects.
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