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

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.

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.

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.