Gatekeepers of immunity: mechanisms and regulation of immune checkpoints and their role in immune-privileged sites.

Immune checkpoints are a diverse group of cell-surface regulators which inhibit immune activation while maintaining self-tolerance. Inhibitory signaling and ligand competition enable molecules like PD-1, CTLA-4, LAG-3, TIM-3, TIGIT, and BTLA to diminish T-cell effector function, decrease pro-inflammatory cytokine production, and encourage exhaustion, inducing changes in cancer and autoimmunity. In tumors, their increased expression in the microenvironment reduces cytotoxic monitoring and is associated with poor outcomes. While treatment blockade can restore anti-tumor responses, it may lead to immune-related side effects. On the other hand, enhancing checkpoint activity may reduce pathogenic inflammation in conditions like systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis, although it could limit antitumor immunity. Besides disease, these checkpoints play a role in maintaining homeostasis in immune-privileged regions, such as the eye, central nervous system, testis, and maternal-fetal interface, where barrier systems, tolerogenic antigen presentation, and suppressive cytokine environments work together to reduce collateral damage. Pathological privileged-like states can also develop in tumors, granulomas, and the gastrointestinal tract, where signals for endothelial apoptosis, metabolic changes, and the promotion of regulatory T-cells strengthen local tolerance. Non-genetic evaluations of pathway activity and cellular impairment aid in differentiating exhaustion from reversible anergy, guiding treatment choices. This review integrates mechanistic, contextual, and clinical aspects of immune checkpoints to elucidate their dual functions as obstacles to antitumor immunity and protections against autoimmunity.