The cGAS-STING signaling in hepatocellular carcinoma: A spatiotemporally gated immune switch linking pro-tumorigenic immune evasion and anti-tumor therapeutic response.

Abstract

Hepatocellular carcinoma (HCC) arises from chronic inflammation and immune tolerance, posing substantial challenges for immunotherapy. The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling is a central immunological hub linking innate immune sensing to adaptive immune responses in tumors. In HCC, cGAS-STING signaling exhibits a context-dependent dual role across multiple hepatic cell types, including hepatocytes, hepatic stellate cells and immune cells, orchestrating both anti-tumor immunity and pro-tumorigenic inflammation. While acute activation enhances dendritic cell maturation, antigen presentation, and CD8+ T-cell priming to boost anti-tumor immunity, sustained or dysregulated cGAS-STING signaling promotes chronic inflammation and subsequently remodels an immunosuppressive tumor microenvironment (TME) to promote tumorigenesis. This dual functionality positions the cGAS-STING signaling as both a therapeutic opportunity and a critical constraint in HCC immunotherapy. Recent advances highlight the translational potential of STING-targeted strategies, including synthetic agonists, combination regimens with targeted therapies, immune checkpoint inhibitors (ICIs) as well as nanomaterial-based delivery systems. At the same time, clinical translation remains constrained by systemic inflammatory toxicity, context-dependent tumor-promoting inflammation, pathway refractoriness or silencing, and the lack of validated biomarkers for patient selection. In this review, we summarize the molecular mechanisms, cell-type-specific functions and intercellular crosstalk of cGAS-STING signaling in HCC, and discuss therapeutic strategies and translational challenges. We propose future directions focusing on spatiotemporal activation, precision delivery, and biomarker-guided interventions to exploit the therapeutic potential of targeting the cGAS-STING signaling in HCC.