Unlocking new horizons in immunity: The roles and mechanisms of immune checkpoints in inflammation regulation

Immune checkpoints (ICs) are receptors that regulate immune responses through both activating and inhibitory mechanisms. Key pathways, including programmed death 1 (PD-1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), T cell immunoreceptor with Ig and ITIM domains (TIGIT), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), and lymphocyte-activation gene 3 (LAG-3), mediate bidirectional interactions between checkpoint signaling and inflammatory networks. The inflammatory microenvironment modulates IC expression through cytokines, metabolites, and oxidative signals, while persistent checkpoint activation promotes immunosuppression. This feedback loop contributes to multiple disease contexts, including cancer, autoimmune disorders, infections, and metabolic inflammation. Immune checkpoint inhibitors (ICIs) not only enhance antitumor immunity but also reshape systemic immune networks, which is closely associated with immune-related adverse events (irAEs). This review summarizes the molecular and cellular mechanisms by which ICs regulate inflammatory responses and highlights their roles across diverse pathological conditions. It further emphasizes the potential of targeting checkpoint–inflammation interactions to improve precision immunotherapy and therapeutic strategies for inflammatory diseases.