A single molecule that straddles the boundary between blood vessel biology and immune regulation is emerging as one of the more intriguing targets in translational oncology. Vascular adhesion protein-1, known to cell biologists as VAP-1 and to genomic databases as amine oxidase copper-containing 3, or AOC3, sits on the surface of endothelial cells, where it performs two jobs at once. It physically captures circulating leukocytes and helps them squeeze through the vessel wall, and it also acts as a semicarbazide-sensitive amine oxidase, catalyzing the oxidative deamination of primary amines to produce aldehydes, ammonia and hydrogen peroxide. That hydrogen peroxide is not metabolic noise. It is a redox signal, and according to a comprehensive new review published in Cancer Cell International, it may help shape the tumor microenvironment in ways that favor cancer growth, immune escape and metastatic spread.
The review, written by Mohammad Amin Karimi, Pouya Mahdavi Sharif and Nima Rezaei of the Universal Scientific Education and Research Network and Tehran University of Medical Sciences, pulls together evidence from experimental models and clinical studies to argue that VAP-1 deserves a place alongside better-known players such as VEGF, PD-L1 and the integrin family in the oncology conversation. The authors were published in the journal’s open-access format on 13 August 2026, and their synthesis arrives at a moment when several VAP-1 inhibitors originally developed for inflammatory disease are being reconsidered for cancer applications. The paper’s central claim is deceptively simple: a molecule that evolved to guide immune cells through inflamed tissue can be co-opted by tumors to build the very vasculature, stroma and immunosuppressive backdrop they need to thrive.
Structurally, VAP-1 is a homodimeric, membrane-bound glycoprotein of roughly 170 kilodaltons, with a large extracellular domain that carries the copper-containing active site and the covalently bound topaquinone cofactor responsible for its enzymatic chemistry. In its adhesive role, the protein engages sialic acid-binding immunoglobulin-like lectins, particularly Siglec-9 on leukocytes, initiating the slow-rolling and firm-adhesion steps that precede transendothelial migration. The enzymatic domain, meanwhile, converts primary amines into products that can diffuse into surrounding tissue, where hydrogen peroxide acts on endothelial cells, stromal fibroblasts and infiltrating immune cells alike. A soluble form of the protein, sVAP-1, circulates in plasma and can be measured by enzyme-linked immunosorbent assay, which is where the biomarker story begins.
Clinically, the review documents a consistent pattern across tumor types. In gliomas, including glioblastoma multiforme, elevated tissue VAP-1 expression tracks with aggressive behavior and unfavorable survival, consistent with the protein’s established role in driving angiogenesis in the setting of hypoxia and vascular proliferation. In breast cancer, colorectal cancer and ovarian cancer, including high-grade serous ovarian carcinoma, the authors find that higher VAP-1 levels in tumor tissue correlate with disease progression and poorer overall survival, with the molecule implicated in stromal remodeling and metastatic seeding. In gastric and thyroid cancers, the picture is somewhat different: what matters there is the circulating concentration of soluble VAP-1, which appears to carry adjunctive diagnostic relevance when interpreted alongside conventional biomarkers, imaging findings and clinicopathological features rather than as a stand-alone test.
The mechanistic heart of the review concerns what VAP-1 actually does inside a tumor. Through its enzymatic output, hydrogen peroxide promotes a pro-angiogenic cascade that complements vascular endothelial growth factor signaling, encouraging the formation of the abnormal, leaky vasculature that characterizes many solid tumors. The same redox signaling appears to bias the immune infiltrate toward suppression. Experimental studies cited in the review describe VAP-1-dependent recruitment of CD11b-positive myeloid cells, granulocyte-marker-positive cells and myeloid-derived suppressor cells, along with a shift in tumor-associated macrophages toward the alternatively activated M2 phenotype, which is associated with tissue remodeling, angiogenesis and dampened antitumor immunity. At the same time, the T helper cell balance tilts from a cytotoxic, Th1-dominated response toward a Th2 profile that is permissive to tumor growth.
Perhaps the most clinically resonant finding is what happens when VAP-1 is blocked. In preclinical models, pharmacological inhibition of the enzymatic activity, using compounds such as PXS-4681A, PXS-4728A, U-V296 and the clinically advanced ASP8232, or antibody-based approaches such as the anti-VAP-1 monoclonal antibody timolumab, reduces angiogenesis, cuts down the infiltration of immunosuppressive myeloid cells and restores the function of CD8-positive cytotoxic T lymphocytes. Crucially, the review highlights synergy when VAP-1 inhibition is combined with immune checkpoint inhibitors, the class of drugs that includes antibodies against PD-1, PD-L1 and CTLA-4. The rationale is straightforward: checkpoint blockade unleashes T cells that are already present, but if the tumor microenvironment is physically and chemically hostile to T cell infiltration in the first place, the drugs cannot work. VAP-1 inhibition appears to open the door, allowing checkpoint inhibitors to act on a more responsive immune landscape.
This framing puts VAP-1 in the same conceptual category as other stromal and myeloid targets currently being explored to widen the benefit of immunotherapy, from TGF-beta inhibitors to CSF1R blockade. What distinguishes VAP-1, however, is its accessibility. Because it is expressed on the luminal surface of endothelial cells, it is directly exposed to the bloodstream, meaning that both therapeutic antibodies and small molecules can reach it without having to penetrate tumor tissue. That same accessibility underpins a second translational avenue: molecular imaging. The review describes the development of VAP-1-specific ligands labeled with positron-emitting isotopes such as gallium-68, which can be used in PET scans to visualize VAP-1 expression in vivo. In principle, such imaging agents could support theranostic applications, allowing clinicians to stratify patients according to the VAP-1 status of their tumors, to select those most likely to benefit from VAP-1-targeted therapy, and to assess therapeutic response in real time rather than waiting for anatomical changes on conventional scans.
The hepatocellular carcinoma literature adds an epidemiological dimension to the story. VAP-1 has long been studied in the context of liver inflammation, where serum levels rise in conditions such as nonalcoholic fatty liver disease, alcoholic liver disease, chronic hepatitis B and C, and primary sclerosing cholangitis. Because hepatocellular carcinoma typically arises on a background of chronic inflammation and fibrosis, the review examines whether VAP-1 contributes directly to liver tumor biology or simply reflects the inflamed, cirrhotic terrain in which liver cancers develop. The emerging picture suggests both are true to some degree: elevated VAP-1 in the diseased liver promotes the vascular and stromal changes that precede malignancy, and continued expression in established tumors sustains the microenvironmental conditions that support their growth.
None of this means VAP-1 is about to become a household name in cancer medicine overnight. The review is candid about the challenges. Biomarker studies vary in design, sample size and the analytical methods used to measure VAP-1, whether by immunohistochemistry on formalin-fixed paraffin-embedded tissue, quantitative polymerase chain reaction, or ELISA on plasma samples, making cross-study comparisons difficult. Circulating sVAP-1 is also elevated in a range of non-cancerous inflammatory, metabolic and cardiovascular conditions, including type 2 diabetes mellitus, chronic kidney disease and heart failure, which limits its specificity as a diagnostic marker and means it must be interpreted in clinical context. On the therapeutic side, drugs developed for inflammatory indications were optimized for different patient populations, dose ranges and safety endpoints, and their efficacy in cancer remains to be demonstrated in properly powered clinical trials. The authors also note that completely suppressing a molecule involved in normal leukocyte trafficking raises questions about long-term immunological consequences that preclinical models cannot fully answer.
What the review ultimately offers is a roadmap. It consolidates evidence that VAP-1 overexpression is a recurring feature of aggressive tumors, that its dual adhesive and enzymatic functions converge on angiogenesis and immune suppression through hydrogen peroxide-mediated redox signaling, and that its blockade can cooperate with checkpoint immunotherapy in preclinical systems. It also points to imaging agents and soluble biomarkers as tools that could bring VAP-1 biology out of the laboratory and into the clinic, enabling patient selection and response monitoring in ways that few stromal targets currently allow. If ongoing translational efforts bear fruit, the molecule that quietly helps immune cells cross blood vessel walls during inflammation may find a second career as a bullseye on the tumor vasculature, a window into the tumor microenvironment and a lever for prying open cancers that have so far resisted the immune system’s advances.
Subject of Research: The role of vascular adhesion protein-1 (VAP-1/AOC3) in cancer progression, diagnosis, prognosis and therapy
Subject of Research: Cancer
Article Title: Vascular adhesion protein-1 (VAP-1) in cancer: mechanisms and translational implications for diagnosis, prognosis, and therapy
Article References: Karimi, M. A., Mahdavi Sharif, P., & Rezaei, N. (2026). Vascular adhesion protein-1 (VAP-1) in cancer: mechanisms and translational implications for diagnosis, prognosis, and therapy. Cancer Cell International. https://doi.org/10.1186/s12935-026-04437-6
Image Credits: AI Generated
DOI: 10.1186/s12935-026-04437-6
Keywords: VAP-1, AOC3, tumor microenvironment, angiogenesis, immune checkpoint inhibitors, hydrogen peroxide, soluble VAP-1 biomarker, immunotherapy, molecular imaging, theranostics, myeloid-derived suppressor cells, oxidative stress
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Nathaniel Bowman. (September 4, 2026). Vascular adhesion protein-1 offers new targets for cancer diagnosis and therapy. Scienmag. https://scienmag.com/vascular-adhesion-protein-1-offers-new-targets-for-cancer-diagnosis-and-therapy/
Nathaniel Bowman. “Vascular adhesion protein-1 offers new targets for cancer diagnosis and therapy.” Scienmag, 4 September 2026, https://scienmag.com/vascular-adhesion-protein-1-offers-new-targets-for-cancer-diagnosis-and-therapy/. Accessed 4 September 2026.
Nathaniel Bowman. “Vascular adhesion protein-1 offers new targets for cancer diagnosis and therapy.” Scienmag. September 4, 2026. https://scienmag.com/vascular-adhesion-protein-1-offers-new-targets-for-cancer-diagnosis-and-therapy/
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