Stress-responsive glucocorticoid receptor signaling shapes the immune tumor microenvironment in lung cancer

Background: Racial disparities continue to exist in lung cancer, while Black individuals tend to smoke less than Whites, indicating potentially additional factors contribute to lung cancer risk. Our previous work showed that social stressors, including neighborhood violent crime, can shape tumor biology via stress-responsive mechanisms. In this study, we investigated how neighborhood violent crime influences tumor microenvironment with a focus on how glucocorticoid receptor activity impacts the spatial pattern of M2 macrophages and CD8⁺ T cells as indicators of hot and cold immune phenotypes. Methods: We analyzed 15 lung tumor spatial transcriptomic samples to quantify pathway activity and cell type associations using gene set co-regulation analysis (GESECA). Spatial co-localization was assessed using univariate and bivariate local Moran's I (p < 0.05). To enhance spatial resolution beyond the Visium spot size, we extracted latent spatial features using non-negative matrix factorization (NMF), estimated empirical variograms to characterize spatial autocorrelation, and applied ordinary kriging to generate high-resolution spatial maps. Results: Neighborhood violent crime rates were positively correlated with glucocorticoid receptor activity, as evidenced by high expression of genes involved in the glucocorticoid biosynthesis pathway activity (p < 0.05). Regions with elevated glucocorticoid receptor activity also showed higher abundance of epithelial cells, especially in tumors from high-crime neighborhoods. High-resolution spatial maps further revealed that tumors from high-violent crime neighborhoods displayed strong co-localization between M2 macrophages and CD8⁺ T cells, suggesting that CD8⁺ T cells are surrounded by immunosuppressive myeloid cells, creating a functionally “cold” tumor microenvironment. In contrast, tumors from low-violent crime neighborhoods showed more mutually exclusive spatial patterns of M2 macrophages and CD8⁺ T cells, reflecting a “hot” tumor microenvironment. Conclusions: Our findings suggest that exposure to social stressors, such as neighborhood violent crime, may influence tumor biology by altering stress-responsive pathways and reshaping immune spatial architecture. The distinct hot and cold immune microenvironment may indicate differential treatment effectiveness across neighborhood contexts, potentially contributing to lung cancer disparities. Different immunotherapy strategies depending on immune tumor microenvironment to improve treatment effectiveness.