Smoking Behavior Is Associated With an Altered Immune Landscape in Prostate Cancer: Implications for Patient Outcomes

ABSTRACT Background Smoking is a modifiable risk factor for prostate cancer (PCa) diagnosis, recurrence, and mortality. While the mutagenic effects of tobacco are well‐documented, the immunological consequences of smoking within the tumor microenvironment (TME) are poorly understood. This study investigates how smoking reshapes the PCa immune landscape and how the associated changes could potentially be associated with patient survival. Methods Tumor tissues from smoker and nonsmoker prostate cancer patients were subjected to multiplex gene expression analysis of immune cell types using the nanoString nCounter® PanCancer immune profiling panel to examine the effect of smoking behavior on the immune landscape. Gene expression data were also analyzed using Enrichr to identify differentially activated pathways in smoker versus nonsmoker patients. Further, we surveyed public databases to examine the association between top differentially‐expressed genes and altered immune cell abundance with patient survival. Results Current‐smokers exhibited significantly higher infiltration of tumor‐associated macrophages (TAMs) ( p = 0.036) and regulatory T cells (Tregs) ( p = 0.045), compared to nonsmokers, with a trend for lower mast cell infiltration ( p = 0.055). A significant positive correlation ( r = 0.42; p = 0.036) was observed between TAMs with Tregs in all samples, with a stronger correlation in current‐smokers ( r = 0.88; p = 0.008) than nonsmokers ( r = 0.26; p = 0.403). A total of 89 DEGs were identified between current‐smokers and nonsmokers, associated with upregulation of immunosuppressive pathways including “primary immunodeficiency” and “PD‐L1 expression and PD‐1 checkpoint,” and downregulation of “antigen‐processing and ‐presentation” and “NF‐kappa‐B signaling” pathways. Key upregulated genes, MAGEA3, POU2AF1, and SEMG1, correlated with immune suppression markers and poorer PCa patient survival. Concomitant high TAM and Treg infiltration also significantly correlated with reduced overall survival ( p = 0.04). No significant differences were observed between current‐smokers and former‐smokers, who exhibited patterns similar to nonsmokers. Conclusions These findings suggest that active smoking creates an immunosuppressive TME, potentially facilitating rapid tumor growth and aggressive progression. Smoking cessation may reverse these changes, highlighting the clinical significance of smoking behavior in disease outcomes.