ATAD2 drives immunotherapy resistance by promoting lactic acid-mediated CD8 T cell dysfunction in lung adenocarcinoma.

[BACKGROUND] T cell-based immunotherapies have improved outcomes in lung adenocarcinoma (LUAD), yet many patients develop primary or acquired resistance. Tumor-intrinsic mechanisms that suppress CD8 T cell function remain incompletely understood.

[METHODS] Public LUAD transcriptomic datasets were analyzed to assess the association of ATPase family AAA domain-containing protein 2 (ATAD2) with prognosis and immune infiltration. -deficient LUAD cell lines were generated using CRISPR/Cas9 and co-cultured with activated CD8 T cells to evaluate cytotoxicity, cytokine production, PD-1 expression and survival. The mediating role of lactic acid (LA) was confirmed using conditioned medium exposure, exogenous LA supplementation, and LDHA overexpression rescue experiments. ATAD2-mediated transcriptional regulation of LDHA was investigated by ChIP-qPCR and c-Myc overexpression. Subcutaneous tumor models were used to determine the effects of deletion on LA accumulation, CD8 T cell infiltration, tumor growth, and response to anti-PD-1 therapy.

[RESULTS] ATAD2 was significantly upregulated in LUAD and correlated with poor survival and decreased CD8 T cell infiltration. deletion enhanced CD8 T cell function and survival, effects reversed by exogenous LA. Mechanistically, ATAD2 enhanced c-Myc-dependent LDHA transcription, leading to increased lactic acid production and an immunosuppressive microenvironment. LDHA overexpression restored LA levels and reversed the immune-activating effects of loss. , deficiency reduced intratumoral LA, remodeled the immunosuppressive microenvironment, increased CD8 T cell infiltration, inhibited tumor growth, and improved sensitivity to anti-PD-1 therapy.

[CONCLUSIONS] ATAD2 drives immunotherapy resistance in LUAD by activating an ATAD2-LDHA-LA axis that impairs CD8 T cell function. Targeting ATAD2 may broadly restore antitumor immunity and enhance the efficacy of T cell-based immunotherapies.