Manganese improves CD8⁺ T cell recruitment via cGAS-STING in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a major cause of cancer-related deaths worldwide. Chemotherapy using cisplatin, a drug that damages deoxyribonucleic acid (DNA), is not very effective in treating HCC due to its side effects and drug resistance. Manganese (Mn²⁺), a trace element, has been shown to enhance immune responses, but its ability to improve cisplatin-induced antitumor immunity in HCC remains unclear. The present study found that treatment with Mn²⁺ in combination with cisplatin promoted cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling activation and C-X-C motif chemokine ligand 10 (CXCL10) production in tumor and dendritic cells. CXCL10 is associated with CD8A levels, and its high expression is linked to better prognosis in patients with HCC. In addition, Mn²⁺ and cisplatin co-treatment enhanced the recruitment of CD8⁺ T cells through the CXCL10/CXCR3 axis. Similarly, in an orthotopic transplantation tumor model, STING activation, CD8⁺ T cell infiltration, and tumor cell killing levels were higher in the combined treatment group. The above findings suggest that utilizing Mn²⁺ in combination with cisplatin could be a potential treatment option for HCC.