<p>Suppression of tumor-reactive CD8⁺ T cells is common within the tumor microenvironment. However, little is known about how tumors systemically affect the overall CD8⁺ T cell compartment. Here we demonstrate that peripheral blood CD8⁺ T cells from patients with lung cancer showed altered compositions particularly within CD45RA⁻CCR7⁻ effector memory subpopulation. Specifically, patients with lung cancer exhibited increased frequency of more differentiated effector memory cells, which are less susceptible to T cell-receptor-induced proliferation. Further analysis using single-cell RNA sequencing revealed that these alterations were correlated with reduced quiescence and increased spontaneous activation at a systemic level, indicative of homeostatic dysregulation of the entire CD8⁺ T cell population. This phenomenon was found to be correlated with a poor clinical response to immune checkpoint inhibitor therapy across four independent cohorts, consisting of a total of 224 patients with lung cancer. These findings suggest that lung cancers continue to counteract potentially tumor-reactive CD8⁺ T cells by inducing homeostatic dysregulation of the entire CD8⁺ T cell compartment systematically.</p>