CircRNAs as central regulators of Immunometabolic crosstalk in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is distinguished by profound metabolic reprogramming and a highly immunosuppressive tumor microenvironment, two hallmarks that cooperatively drive tumor progression and therapeutic resistance. While metabolic rewiring and immune escape have traditionally been studied as parallel processes, the molecular regulators that integrate these pathways remain incompletely defined. Circular RNAs (circRNAs) are a type of covalently closed non-coding RNAs with exceptionally stable and regulatory versatility, and have recently emerged as critical modulators of both cancer metabolism and immune signaling. However, their coordinated role at the intersection of metabolism and immunology in HCC has not been systematically synthesized. This review provides a comprehensive, mechanistic framework that positions circRNAs as central regulators of immunometabolic crosstalk in HCC. We summarize how circRNAs modulate glycolysis, lipid remodeling, glutamine metabolism, and redox balance while simultaneously regulating immune checkpoint pathways, macrophage polarization, T-cell depletion, and NK-cell dysfunction. We further discuss exosomal circRNAs as mediators of tumor-immune communication and remodeling of the tumor microenvironment, linking metabolic stress responses to adaptive immune suppression. Importantly, we highlight circRNA-driven immunometabolic circuits as contributors to resistance against immune checkpoint inhibitors and metabolic therapies. By integrating metabolic, immune, and translational perspectives, this review identifies key knowledge gaps, including context-dependent circRNA functions, challenges in detection standardization, and the need for multi-omic stratification strategies. We propose that targeting circRNA-mediated immunometabolic networks represents a promising frontier for precision therapy in HCC.