Background <p>Psychological stress can affect the incidence and mortality of non-small cell lung cancer. However, how stress influenced tumor immunity, especially tumor-infiltrating CD8⁺ T cells, is still unclear.</p> Methods <p>We constructed anxiety-like model with acute restraint stress and evaluated behaviors of mice through open-field test, light–dark box test and forced swimming test. Flow cytometry was performed to detect the proportion of immune cells in tumor tissues, immunofluorescence to explore the expression of related proteins, smart RNA sequence and qRT-PCR to monitor the relative genes in RNA levels, and ELISA to measure hormone concentrations in mouse serum.</p> Results <p>We observed that acute restraint stress can cause anxiety-like behaviors in mice and promote the progression of non-small cell lung cancer. Stress suppressed the expression of TNF-α, IFN-γ, granzyme B and Ki67, and induced an upregulation of PD-1⁺, LAG3⁺ and TIM-3⁺ CD8⁺ T cells. The surge on corticosterone in blood and its corresponding receptor in tumors consequent upon stress are positively correlated with tumor growth. Similarly, glucocorticoid receptor inhibitor RU486 restrained tumor growth in vivo. Specifically, RU486 reversed pro-tumor ability and CD8⁺ T cell exhaustion induced by corticosterone in vitro. Consistently, smart RNA sequence and enrichment analyses indicated that stress-induced pro-tumor effects were partially attributed to T cell receptor signaling pathway.</p> Conclusions <p>In brief, our study demonstrates that stress–corticosterone axis induces exhaustion of tumor-infiltrating CD8⁺ T cells, contributing to accelerated progression of non-small cell lung cancer.</p>