Hepatocellular carcinoma (HCC) is one of the most lethal cancers, usually diagnosed at an advanced stage. Metabolic reprogramming plays a significant role in HCC progression, probably related to immune evasion, yet the key gene is unclear. In this study, six metabolism-related genes with prognostic implications were screened. Correlation analysis between the key genes and immune cell subtypes was conducted, and a prominent gene strongly associated with immunosuppression, SLC16A3, was identified. Overexpression of SLC16A3 is associated with the loss of T-cell function and might lead to the upregulation of several immunosuppressive proteins. Gene function enrichment analysis showed genes correlated with SLC16A3 primarily involved in cell adhesion. Single-cell analysis showed that the SLC16A3 gene was mainly expressed in macrophages, especially some tumour-promoting macrophages. Further analysis of spatial transcriptome data indicated that SLC16A3 was enriched at the tumour invasion front. The mIHC revealed that patients with high SLC16A3 expression exhibited significantly reduced infiltration of GZMB+ cells. And SLC16A3 inhibitors significantly suppressed the proliferation of HCC, while simultaneously enhancing T-cell cytotoxicity and reducing exhaustion. These results reveal the phenomenon of immune escape mediated by metabolic reprogramming and suggest that SLC16A3 may serve as a novel target for intervention.© 2024 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.