Host Determinants of Immune Checkpoint Inhibitor Efficacy: Immune, Genetic, Metabolic, and Lifestyle Factors

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment by enhancing antitumor immune responses; however, clinical outcomes remain highly variable across patients and tumor types. While tumor-intrinsic factors such as PD-L1 expression and tumor mutational burden provide some predictive value, they do not fully explain response heterogeneity. Increasing evidence highlights the critical role of host-related determinants in modulating ICI efficacy. This review provides a comprehensive overview of key host factors, including baseline immune competence, T-cell repertoire diversity, cytokine profiles, and peripheral biomarkers. It further examines the impact of germline genetics, HLA genotype, and epigenetic regulation on immune responses. The role of the gut microbiome and its metabolites is explored, alongside the impact of metabolic status, obesity, nutrition, and lifestyle behaviors. Additionally, the effects of co-medications and comorbidities are discussed. Integrating these host-related factors may improve patient stratification and support the development of personalized immunotherapy strategies.