The regulatory role of the renin-angiotensin system in the tumor microenvironment and immunotherapy of hepatocellular carcinoma

Abstract

The renin–angiotensin system (RAS) plays a pivotal role in the initiation and progression of hepatocellular carcinoma (HCC). Through its regulation of angiogenesis, tissue fibrosis, and immune cell activity, RAS profoundly shapes the tumor microenvironment (TME), thereby promoting tumor growth and metastasis. Activation of RAS enhances tumor vascularization while concurrently suppressing anti-tumor immune responses, contributing to immune evasion. Preclinical studies have demonstrated that RAS inhibitors can counteract these pro-tumorigenic processes by remodeling the TME and enhancing immune cell infiltration. Our summary indicates that treatment with RAS inhibitors synergizes with immune checkpoint blockade, markedly strengthening anti-tumor immunity and improving therapeutic efficacy in experimental models. Although the clinical benefits of RAS inhibitors as monotherapy remain limited, their integration with immunotherapy, targeted agents, or anti-angiogenic therapies has revealed considerable synergistic potential. Future research should aim to elucidate the precise mechanisms by which RAS regulates immune modulation in HCC and to optimize combination regimens that enable more effective and personalized therapeutic strategies for patients.