Lactate Metabolic Reprogramming Mediated by CircRNA–LDHA Complex Facilitates Innate Immune Evasion of Liver Cancer

Hepatocellular carcinoma (HCC) exhibits a distinctive metabolic profile that engenders a highly immunosuppressive tumor immune microenvironment, posing significant challenges for targeted therapy. Notably, natural killer (NK) cells, which are abundant in the liver and play a crucial role in innate immunity, are attracting growing attention in HCC immunotherapy. Previously, circular RNAs (circRNAs) have emerged as significant regulators in tumor development. Here, an in vitro NK-cell-driven tumor evolution model is innovatively established and a novel circRNA, circSMPD4 is identified, which induces lactate metabolic reprogramming in tumor, ultimately promoting immune evasion and metastasis. Lactate dehydrogenase A (LDHA), a main subunit of the critical enzyme in lactate metabolism, is identified as the core effector of circSMPD4's biological function. Mechanistically, circSMPD4 physically combines LDHA to reduce its acetylation levels via SIRT2-dependent deacetylation and thus preventing its degradation from chaperone-mediated autophagy-lysosome pathway. These findings unveil an oncogenic circRNA and elucidate a novel regulatory mechanism by which tumor cell metabolic reprogramming facilitates tumor immune evasion and tumor progression.