<p>Immune evasion and immunosuppression are important hallmarks of human malignancies. Astragaloside IV (AST) is one of the effective ingredients in <i>Astragalus</i>, which has been confirmed to enhance antitumor immunity. However, the functions and underlying mechanism of AST on oral squamous cell carcinoma (OSCC) tumorigenesis remain undetermined. Our present work tried to test whether and how AST inhibited OSCC immune evasion and ameliorated CD8⁺ T cell-mediated antitumor response in immune microenvironment. The results of the present work indicated that AST repressed OSCC cells’ proliferation and migration in dosage-dependent manner. In a co-culture system analysis of CD8⁺ T and OSCC cells, AST enhanced the antitumor activity of CD8⁺ T cells to impair the OSCC immune evasion. Moreover, AST also repressed the lactate secretion and extracellular acidification. Furthermore, excess lactate accumulation triggered the PD-L1 enrichment on OSCC cells in acidic microenvironment. Mechanistically, AST targeted MCT1 to degrade its mRNA stability, thereby mitigating the extracellular acidification and inhibiting the escape of OSCC from CD8⁺ T cells’ killing. This study indicates that AST could ameliorate the acidic microenvironment in OSCC to improve CD8⁺ T cell-mediated antitumor immune response. Our finding might offer novel insights for the anti-tumor effect of AST and provide a potential therapeutic strategy for OSCC.</p>