Intrapatient variation in PD-L1 expression and tumor mutational burden and implications for outcomes to immune checkpoint inhibitor therapy in patients with non-small-cell lung cancer

Abstract The recent study by Di Federico et al provides valuable insights into the intrapatient heterogeneity of programmed death-ligand 1 (PD-L1) expression and tumor mutational burden (TMB) in non-small cell lung cancer (NSCLC), and its potential impact on responses to immune checkpoint inhibitors. This commentary examines several biological factors that may contribute to such variability, including cytokine signaling, metabolic changes within the tumor microenvironment, and intrinsic tumor heterogeneity. We also consider possible interactions between PD-L1 and TMB in the context of immune evasion. Furthermore, we highlight the need for more rigorous patient stratification in future studies and suggest that dynamic monitoring tools like liquid biopsy could enhance clinical decision-making. A deeper understanding of biomarker variability mechanisms may ultimately support more precise and effective personalized immunotherapy strategies for NSCLC.