<p>Despite identifying specific CD8⁺ T cell subsets associated with immunotherapy resistance, the molecular pathways driving this process remain elusive. Given the potential role of CD38 in regulating CD8⁺ T cell function, we aimed to investigate the accumulation of CD38⁺CD8⁺ T cells in lung cancer and explore its role in immunotherapy resistance. Phenotypic analysis of tumoral CD8⁺ T cells from both lung cancer patients and immunotherapy-resistant preclinical models revealed that CD38-expressing CD8⁺ T cells consist of CD38^hi and CD38^int subsets. These cells exhibited higher expression of exhaustion markers and displayed dysregulated mitochondrial bioenergetics. Notably, increased levels of CD38^hiCD8⁺ T cells in the peripheral, but not central, tumor microenvironment were associated with a favorable response to anti-PD-1 therapy in non-small-cell lung cancer and correlated with the depth of clinical regression. This was evidenced by the greater depletion of CD38^hiCD8⁺ T cells in patients with higher regional CD38^hiCD8⁺ T cell infiltration. In immune checkpoint blockade (ICB)-resistant murine lung cancer models, PD-L1 mAbs alone failed to effectively reduce CD38^hiCD8⁺ T cell levels. Notably, combination therapy with PD-L1 mAbs and EGCG selectively restricted CD38^hiCD8⁺ T cell infiltration and enhanced IFN-γ production, significantly improving survival in this carcinoma model. The restoration of immunotherapy sensitivity was linked to improved mitochondrial function in CD38^hiCD8⁺ T cells, which was validated by the established relationship between IFN-γ production and mitochondrial metabolism. Collectively, our data highlight the role of CD38-coupled mitochondrial dysfunction in promoting CD8⁺ T cell exhaustion and intrinsic resistance to ICB therapy, thereby offering a rationale for targeting CD38 to enhance the therapeutic efficacy of PD-1 blockade in lung cancer.</p>