<p>Cytotoxic CD8⁺ T lymphocytes play a pivotal role in anti-tumor immunity by eliminating cancer cells. <i>Sargentodoxa cuneata</i> (Sar) has demonstrated anti-cancer potential. This study investigated the therapeutic potential of Sar in lung adenocarcinoma (LUAD) through its modulation of CD8⁺ T cell tumoricidal capacity. CD8⁺ T cells were isolated and co-cultured with treated HCC2935 and H1975 LUAD cell lines. The influences on LUAD cells were assessed by detecting cell viability and apoptosis. The impacts on CD8⁺ T cells were evaluated by measuring cell cytotoxic activity and IFN-γ and TNF-α secretion. The aminoacylase-1 (ACY1)/arginase-2 (ARG2) interaction was predicted by molecular docking and confirmed by GST pull-down and Co-IP assays. Animal xenograft experiments were used to analyze the therapeutic potential of Sar in vivo. ACY1 and ARG2 were upregulated and positively associated with PD-L1 expression in LUAD samples. Mechanistically, ACY1 physically interacted with ARG2 in LUAD cells. ACY1 inhibited apoptosis in LUAD cells and attenuated cytotoxic activity of CD8⁺ T lymphocytes via ARG2. Moreover, Sar induced LUAD cell apoptosis and enhanced CD8⁺ T cell cytotoxicity by downregulating ACY1 in vitro. Sar attenuated xenograft tumor development through ACY1 downregulation in vivo. Our study establishes that Sar emerges as a promising therapeutic agent in LUAD by enhancing CD8⁺ T tumoricidal capacity through targeting the ACY1/ARG2 co-regulatory axis.</p> Graphical abstract <p><i>Sargentodoxa cuneata</i> (Sar) reduces ACY1 expression to disrupt the ACY1/ARG2 interaction and thus downregulates PD-L1, consequently inducing LUAD cell apoptosis and enhancing CD8⁺ T cell cytotoxicity.</p> <p></p>