SLC16A3 (MCT4) expression in tumor immunity and Metabolism: Insights from pan-cancer analysis

SLC16A3, a highly expressed H + -coupled symporter, facilitates lactate transport via monocarboxylate transporters (MCTs), contributing to acidosis. Although SLC16A3 has been implicated in tumor development, its role in tumor immunity remains unclear.

A pan-cancer analysis was conducted using datasets from The Cancer Genome Atlas, Cancer Cell Line Encyclopedia, and Genotype-Tissue Expression projects. SLC16A3 expression patterns and associations with tumor progression, prognosis, immune checkpoints, and immune neoantigens were evaluated across 30 cancer types. Immune infiltration scores were analyzed using the Tumor Immune Estimation Resource dataset.

SLC16A3 expression is differentially regulated in cancer versus healthy tissues, with elevated levels associated with poor prognosis and reduced overall survival in glioblastoma multiforme (HR = 1.88), low-grade gliomas (HR = 1.51), and lung adenocarcinoma (HR = 1.33). Notably, significant associations between SLC16A3 expression and poor outcomes were observed in 33 cancers, except for rectum adenocarcinoma, testicular germ cell tumors, pheochromocytoma and paraganglioma, and adrenocortical carcinoma. SLC16A3 expression was also strongly linked to immune checkpoints and neoantigens. Correlations with tumor-infiltrating immune cells were pronounced in prostate adenocarcinoma but absent in uterine carcinosarcoma and cervical squamous cell carcinoma. Gene set enrichment analysis (GSEA) revealed a pivotal role of SLC16A3 in tumor growth, metabolism, and immunity.

SLC16A3, the transporter facilitating the efflux of lactic acid, shows differential expression across various cancer types and exerts a critical effect on tumor development and immunity. Thus, SLC16A3 has promising potential as a prognostic marker, and its targeted manipulation can offer therapeutic advantages.