CCT2 Orchestrates Glycolysis and Exosome-Mediated M2 Macrophage Polarization in HCC tumorigenesis

Introduction: Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with a poor prognosis, driven by metabolic reprogramming and immune evasion. The role of T-complex protein 1 subunit beta (CCT2) in HCC remains unclear. This study aimed to elucidate the function of CCT2 in HCC tumorigenesis. Methods: experiments to investigate CCT2's role in HCC metabolism and immune modulation. The glycolytic activity was assessed by measuring extracellular acidification rate, glucose uptake, lactate levels, and metabolomic profiles. Coimmunoprecipitation or GST pulldown assays confirmed CCT2 interactions with aldolase A (ALDOA) and glutathione S-transferase P (GSTP1), while THP1 co-culture assays evaluated tumor immune crosstalk. Results: . Furthermore, co-culture and exosome treatment experiments reveal that CCT2 promotes M2 macrophage polarization and establishes an immunosuppressive tumor microenvironment through coordinated metabolic and exosome-mediated mechanisms. In mouse models, CCT2 knockdown significantly enhances the antitumor efficacy of PD-1 blockade. Conclusions: CCT2 stabilizes ALDOA and facilitates exosome-mediated immunosuppressive signaling, thereby linking metabolic reprogramming to immune evasion in HCC and supporting its potential as a mechanistically informed therapeutic target.