Foxp3⁺ Tregs in HCC immunity and immunotherapy

Hepatocellular carcinoma (HCC) arises within an immunologically complex, tolerogenic microenvironment, where CD4⁺ CD25⁺ Foxp3⁺ regulatory T cells (Tregs) suppress antitumor immunity, sustain inflammation, and promote pathological angiogenesis and tumor progression. We delineate how the unique metabolic and cytokine landscapes of HCC stabilize highly suppressive Treg subsets and highlight phenotypic and metabolic differences between Tregs driven by viral versus nonviral liver diseases. We discuss Treg heterogeneity and the prognostic and predictive value of circulating and intratumoral Treg metrics, together with emerging strategies to target tumor-resident Tregs while preserving peripheral tolerance. Finally, we examine how modern combination immunotherapies reshape Treg dynamics, emphasizing the need to balance enhanced antitumor efficacy with the risk of immune-related liver and systemic toxicities.