Immunohistochemical analysis of p53 and LKB1 as predictive biomarkers of immune checkpoint inhibitor response in non-small cell lung cancer.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are a mainstay in the treatment of non-small cell lung cancer (NSCLC). Although accurate predictive biomarkers are required for treatment selection-considering the risk of serious immune-related adverse events-such predictors remain limited. In this study, we aimed to evaluate the association between the expression of p53, LKB1, and NRF2 proteins and ICI efficacy. METHODS: This retrospective analysis included patients with NSCLC who received first-line ICI-based therapy or epidermal growth factor receptor-tyrosine kinase inhibitors between 2017 and 2025 at our institute. Immunohistochemistry was performed on diagnostic samples to assess p53, LKB1, and NRF2 expression and tumor-infiltrating lymphocytes (TILs). Additionally, the associations between biomarker expression and clinical outcomes were examined. RESULTS: Among the 43 evaluable cases in the ICI group, aberrant p53 expression was observed in 46.5%, LKB1 loss in 13.9%, and nuclear-dominant NRF2 expression in 34.9% of cases. Aberrant p53 expression was associated with increased TILs and improved progression-free survival (PFS), while the loss of LKB1 was correlated with an immunosuppressive microenvironment and shorter PFS. Nuclear-dominant NRF2 expression was associated with poorer overall survival. CONCLUSIONS: The immunohistochemical profiles of p53 and LKB1 are associated with distinct immune microenvironment features. These markers may serve as surrogate predictors of ICI efficacy in patients with NSCLC.