Immune checkpoint inhibitors in infectious diseases: therapeutic reinvigoration, immunopathology, and precision targeting.

Immune checkpoint inhibitors (ICIs) have transformed cancer therapy by releasing inhibitory pathways that restrain antitumor T-cell responses. Their success has renewed interest in checkpoint blockade for infectious diseases, particularly chronic viral infections, sepsis-associated immunosuppression, and refractory opportunistic infections. In these settings, immune checkpoints may contribute to pathogen persistence by limiting effector function, but they also restrain tissue injury, cytokine excess, and immune-mediated organ damage. This dual role makes translation fundamentally different from oncology: the goal is not maximal immune activation, but controlled immune recalibration. Evidence is strongest for chronic viral infections and selected oncology-adjacent cohorts, whereas infection-directed trials remain early and heterogeneous. A precision framework based on pathogen burden, immune phenotype, tissue vulnerability, biomarker feasibility, safety monitoring, and implementation context is therefore essential before ICIs can be responsibly developed as host-directed therapies for infectious diseases. This review synthesizes the rationale, evidence, and safety considerations for ICIs in infectious diseases. We discuss chronic viral infections, including human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), and Epstein-Barr virus (EBV), and highlight EBV as a bridge between persistent viral infection, immune surveillance, lymphoproliferation, and cancer immunotherapy. We also examine tuberculosis, sepsis, fungal infections, and parasitic diseases, where checkpoint pathways may restore host defense or amplify immunopathology. Finally, we propose a precision-immunotherapy framework integrating pathogen biology, immune phenotype, tissue risk, biomarker feasibility, access, and trial design.