Unlocking the potential of targeting the angiotensin II type 1 receptor in cancer

The renin-angiotensin system is a key regulator of blood pressure homeostasis, with its primary effector, the angiotensin II type 1 receptor (AT1R), mediating vasoconstriction and processes fundamental to cancer progression, including proliferation, angiogenesis, and metastasis. Elevated AT1R expression is consistently linked to poor prognosis and therapeutic resistance across various malignancies. Preclinical studies provide compelling evidence that AT1R activation drives key cancer related processes, while its inhibition by angiotensin receptor blockers (ARBs) suppresses tumour growth, induces apoptosis, reduces angiogenesis, and inhibits metastasis across a wide range of cancer models. Critically, ARBs effectively modulate the tumour microenvironment (TME), alleviating fibrosis, promoting anti-tumour immune cell phenotypes, and enhancing the efficacy of targeted therapies, chemotherapies, and immunotherapies. Despite this strong preclinical evidence and supporting retrospective population studies, clinical translation of ARBs in oncology remains inconsistent, with trials often limited by design, patient heterogeneity, and supra-therapeutic ARB dosages required for acute anti-cancer effects. This review seeks to summarise the current understanding of AT1R's role in cancer, highlight preclinical and clinical investigations of targeting RAS, and suggest further strategies to unlock its therapeutic potential. Realising the full therapeutic promise of AT1R targeting in oncology requires a multifaceted approach, including the development of innovative delivery systems, such as TME-activated ARBs, and the exploration of advanced therapeutic modalities, such as antibody based AT1R inhibitors. Rigorously designed clinical trials that include biomarker-driven patient stratification to identify responsive cohorts are crucial to define the context-dependent role of AT1R and conclusively establish its clinical utility as a combinatorial strategy to enhance patient outcomes.