Coordinated modulation of glucose metabolism and immunity via metal-drug nanovesicles for hepatocellular carcinoma therapy.

A highly immunosuppressive microenvironment, along with disordered glucose metabolism, promotes immune evasion and compromises the effectiveness of cancer immunotherapy. To address these challenges, we developed a multifunctional C-B-M-Mn nanovesicle platform to disrupt tumor metabolism and enhance antitumor immunity. This system encapsulated BAY-876 (a Glut1 inhibitor) and MSA-2 (a STING agonist) in the nanovesicle membrane and incorporated Mn through chelation with gallic acid-modified chitosan oligomers within the nanovesicle core. Under acidic tumor conditions, the surface potential of the nanovesicles shifted to positive charge, facilitating cellular uptake. Once internalized by tumor cells, C-B-M-Mn released its cargo in response to acidic pH and high esterase activity. BAY-876-mediated glycolysis inhibition increased reactive oxygen species (ROS) production and triggered the release of mitochondrial DNA, thereby priming the cGAS-STING signaling pathway. Mn enhanced cGAS sensitivity, while MSA-2 further activated STING, promoting dendritic cell (DC) maturation and CD8 T and natural killer (NK) cell recruitment. In addition, this metabolic blockade reduced PD-L1 expression levels and mitigated immune evasion. Additionally, Mn provided MRI contrast enhancement, enabling simultaneous imaging and treatment. Collectively, these findings highlight the C-B-M-Mn platform as a promising strategy for integrated glucose metabolic inhibition and immunotherapeutic intervention to improve hepatocellular carcinoma (HCC) treatment.