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In 1971, surgeon and scientist Judah Folkman proposed something then considered radical: that solid tumors cannot grow beyond a few millimeters without recruiting their own blood supply — a process called angiogenesis. Inhibit that supply, he argued, and you starve the tumor. Decades of skepticism gave way to vindication when bevacizumab, the first anti-VEGF monoclonal antibody, received FDA approval in 2004. But the research that followed has been far more complicated than anyone anticipated.

A 2026 review published in Frontiers in Immunology traces the full arc of anti-angiogenic oncology: its early brilliance, its clinical disappointments, and the emerging paradigm that may finally unlock its transformative potential. The key insight? Angiogenesis and immunity are not parallel battlefields. They are the same battlefield.

Angiogenesis, the formation of new blood vessels from existing ones, is a tightly regulated physiological process critical for wound healing, development, and reproduction.

In cancer, this process is hijacked. As tumors expand, they rapidly outpace their oxygen supply, creating hypoxic cores. In response, tumor cells upregulate vascular endothelial growth factor-A (VEGF-A), the master regulator of new vessel formation.

The VEGF-A/VEGFR-2 axis is the anchor:

VEGF-A binds to receptor tyrosine kinase VEGFR-2 on endothelial cells → triggering proliferation, migration, and tube formation → creating chaotic capillary networks.

These tumor-associated vessels are structurally abnormal — leaky, poorly perfused, tortuous — and their dysfunction creates far more than just a blood supply problem. They generate the immunosuppressive, hypoxic microenvironment in which tumors thrive and immune cells fail.

This vascular-immune crosstalk is the central revelation of the past decade. "Anergic" tumor endothelial cells downregulate adhesion molecules like VCAM-1 and ICAM-1, physically preventing T-lymphocyte extravasation into tumor tissue. Meanwhile, elevated VEGF suppresses dendritic cell maturation and expands immunosuppressive regulatory T cells and myeloid-derived suppressor cells. The tumor's blood supply is, in effect, its immune shield.

The review examines the next generation of anti-angiogenic agents: bispecific antibodies that simultaneously neutralize VEGF and block PD-(L)1 immune checkpoint pathways within a single molecule. This dual-targeting approach has several theoretical advantages over administering two separate antibodies.

The leading candidate, ivonescimab (AK112/SMT112) — a tetravalent construct combining an anti-VEGF IgG with two anti-PD-1 single-chain variable fragments — has produced striking results. In the randomized Phase 3 trial, in PD-L1-positive non-small cell lung cancer, ivonescimab delivered 2x the disease-free time in a comparison to the current immunotherapy gold standard.

The anti-PD-L1 class, represented by BNT327/pumitamig (BioNTech/BMS), employs the following strategy: because PD-L1 is overexpressed on tumor cells and within the tumor microenvironment, anti-PD-L1 binding preferentially concentrates VEGF neutralization at the tumor site rather than systemically, potentially reducing vascular side effects. Multiple Phase 3 trials are now enrolling across NSCLC, SCLC, triple-negative breast cancer, and colorectal cancer.

Trispecific formats are also entering trials, simultaneously targeting VEGF + PD-1 + CTLA-4 or VEGF + PD-L1 + TGF-β, adding further immunomodulatory pressure on the tumor microenvironment from a single molecule.

The tumor microenvironment (TME) is increasingly understood as the primary determinant of whether immunotherapy succeeds or fails. A hypoxic, poorly vascularized TME excludes immune effector cells, metabolically exhausts those that do infiltrate, and supports the expansion of immunosuppressive populations. VEGF blockade can reverse this: normalizing vessel architecture, reducing hypoxia, improving T-cell infiltration, and reshaping the balance toward anti-tumor immunity.

The review highlights a critical nuance: the outcome depends on dose and sequence. Chronic VEGF inhibition can paradoxically worsen hypoxia via vessel pruning. Short-course, lower-dose anti-VEGF treatment appears to transiently normalize vasculature and may be optimal when combined with immunotherapy. Mathematical modeling supports concurrent rather than sequential dosing when the goal is vascular normalization and improved immune cell trafficking.

Beyond NSCLC, regulatory approvals and ongoing trials are extending these insights across renal cell carcinoma, hepatocellular carcinoma, colorectal cancer, triple-negative breast cancer, and endometrial cancer — suggesting the VEGF-immune axis is a broad dependency of solid tumor oncology, not a disease-specific quirk.

While no dietary approach can replicate the potency of a monoclonal antibody, a growing and rigorous body of evidence demonstrates that specific dietary bioactives modulate pro- / anti-angiogenic signaling and that chronically elevated VEGF expression is partly driven by modifiable metabolic factors.

Adipose tissue, particularly visceral fat, is a significant source of VEGF, leptin, and pro-inflammatory cytokines that collectively sustain a low-grade pro-angiogenic environment. Hyperinsulinemia and elevated IGF-1, hallmarks of metabolic syndrome, are known activators of VEGF transcription via the PI3K/AKT/mTOR pathway. Caloric excess and sedentary behavior chronically maintain the biochemical conditions that support tumor vasculogenesis. Conversely, caloric restriction, weight normalization, and aerobic exercise reduce circulating VEGF, improve immune surveillance, and shift the systemic balance toward anti-angiogenic endogenous mechanisms.

Several well-characterized food compounds interfere with angiogenic signaling:

Resveratrol → red grapes, blueberries, 70% dark chocolate → Inhibits VEGF expression

Epigallocatechin-3-gallate (EGCG) → Green tea →Blocks VEGFR-2 phosphorylation; inhibits endothelial cell migration and tube formation

Curcumin → Turmeric (Curcuma longa) → Downregulates VEGF, bFGF, and angiopoietin; NF-κB inhibition reduces pro-angiogenic cytokines

Moderate-intensity aerobic exercise produces a transient, physiologically normative VEGF signal followed by a net reduction in resting VEGF levels and improved vascular architecture. Exercise also increases natural killer cell activity, CD8+ cytotoxic T-cell mobilization, and systemic anti-inflammatory cytokine profiles, effects that mechanistically complement the goals of immunotherapy. Emerging evidence suggests exercise during cancer treatment may improve immunotherapy response rates, though large-scale trial data are still maturing.

Beyond PD-L1 expression, we currently lack validated predictive markers for which patients will benefit from VEGF x PD(L)1 biospecific therapy. The authors call for integration of angiogenic signatures, tumor hypoxia scoring (including non-invasive PET-based hypoxia imaging), and single-cell RNA sequencing-derived endothelial subpopulation profiling into clinical trial designs, data that will be essential for precision patient selection.

Don’t miss this weeks youtube video with our mascot Dr. Angio bringing complex health and research topics to life.

A highlight for Dr. Vincent W. Li, Chief Operating Officer and Scientific Director of the Angiogenesis Foundation, presenting his work on microfluidic jet therapy at the SAWC conference, showcasing innovative approaches to wound care and ulcer treatment.

Best wishes,
- The Angiogenesis Foundation

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Check out the Angiogenesis Foundation Green Tea from Harney & Sons to support your vascular health.

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