Immune checkpoint molecules beyond PD-1 and CTLA-4: emerging targets in autoimmune diseases and cancer immunotherapy.

BACKGROUND: Immune checkpoint molecules are pivotal regulators of immune activation and tolerance, playing critical roles in cancer, autoimmunity, infectious diseases, and transplantation. While programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) remain the most extensively studied checkpoints, immune checkpoint receptors beyond PD-1 and CTLA-4, including LAG-3, TIM-3, TIGIT, VISTA, BTLA, CD160, and CD96 have expanded our understanding of immune regulation. These pathways not only mediate immune evasion in tumors but also contribute to impaired tolerance in autoimmune diseases.

KEY FINDINGS: Recent preclinical and clinical evidence highlights the potential of novel and next-generation checkpoint inhibitors (ICIs), either alone or in combination with established PD-1/CTLA-4 therapies, to overcome resistance in oncology. Concurrently, agonistic checkpoint modulation is being explored as a precision immunosuppressive strategy in autoimmune disorders, targeting dysregulated T-cell activation while preserving protective immunity. Key challenges remain, including heterogeneity in patient responses, immune-related adverse events (irAEs), and the need for robust biomarkers to guide personalized therapy. Advances in multi-omics profiling, artificial intelligence, and single-cell immune mapping promise to refine patient selection and optimize therapeutic regimens. Furthermore, the application of checkpoint modulation in chronic infections and transplantation underscores its broader potential beyond oncology.

CONCLUSIONS: This review comprehensively discusses the mechanistic basis, therapeutic implications, combination strategies, and future directions of immune checkpoints beyond PD-1 and CTLA-4, emphasizing biomarker development, precision medicine approaches, and balancing efficacy with safety.