Abstract
Immune checkpoint blockade therapy has revolutionized the treatment of metastatic and solid tumours, achieving durable responses in a subset of patients. However, most patients do not respond to immune checkpoint blockade, underscoring the critical need to better understand the determinants of therapeutic efficacy. A key obstacle to effective antitumour immune responses is the abnormal structure and function of tumour-associated blood vessels, which impede immune cell infiltration and contribute to the development of an immunosuppressive tumour microenvironment. Current research highlights the inverse correlation between angiogenesis and immune activity within the tumour microenvironment. In this Review, we discuss tumour angiogenesis in the context of tumour immunity, examining how this affects tumour progression and immunotherapy outcomes. We examine the molecular mechanisms underlying the crosstalk between angiogenesis and tumour immunity and discuss emerging anti-angiogenic regulators that hold potential for combination therapies. By integrating insights from preclinical and clinical studies, we outline future research directions to address current challenges and optimize cancer treatment strategies through combined anti-angiogenic and immunotherapeutic approaches.
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Acknowledgements
Research support is provided by the NIH HL55337 and CA271714. We apologize to colleagues whose work could not be cited due to space limitations. Artificial intelligence was used to tidy up the language and correct grammatical errors before submission of the manuscript.
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Glossary
- High endothelial venules
-
(HEVS). A specialized post-capillary venule that occurs in secondary lymphoid organs, except the spleen, and in other non-lymphoid tissues under certain chronic inflammatory conditions. HEVs allow a high level of extravasation of lymphocytes from blood as a consequence of the constitutive expression of adhesion molecules and chemokines at their luminal surface.
- ‘M2-like’ macrophage phenotype
-
‘M1’ and ‘M2’ are classifications historically used to define macrophages activated in vitro as pro-inflammatory (when ‘classically’ activated with interferon-γ and lipopolysaccharide) or anti-inflammatory (when ‘alternatively’ activated with IL-4 or IL-10). However, in vivo macrophages are highly specialized and extremely heterogeneous with regards to their phenotypes and functions, which are continuously shaped by their tissue microenvironment. The M1/M2 classification is too simplistic to explain their true nature, but these terms are still often used to indicate whether the macrophages in question are more pro-inflammatory or anti-inflammatory.
- Micrometastases
-
Small clusters of cancer cells that have spread from the primary tumour to distant organs or lymph nodes but are too small to be detected by standard imaging techniques. These microscopic cancer cells can remain dormant for years before potentially growing into larger, detectable metastatic tumours.
- Tertiary lymphoid structures
-
(TLSs). Ectopic lymphoid aggregates that are generated in non-lymphoid organs during the process of chronic immune stimulation and that exhibit the structural characteristics of secondary lymphoid organs. TLSs are composed of T cells, B cells and dendritic cells in a specified structural pattern, and often include high endothelial venules.
- Vascular normalization window
-
A temporary period during anti-angiogenic therapy when abnormal, leaky tumour blood vessels are partially restored to a more normal structure and function. This creates an optimal time frame for enhanced drug delivery and immune cell infiltration, improving the effectiveness of cancer treatments.
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Kabir, A.U., Subramanian, M., Kwon, Y. et al. Linking tumour angiogenesis and tumour immunity. Nat Rev Immunol (2025). https://doi.org/10.1038/s41577-025-01211-z
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DOI: https://doi.org/10.1038/s41577-025-01211-z
