CD28 and ICOS in immune regulation: Structural insights and therapeutic targeting.

CD28 and ICOS are key immune checkpoints that regulate T-cell activation, differentiation, and immune tolerance. Their dysregulation contributes to cancer immune evasion, autoimmune diseases, and chronic inflammation, making them critical targets for therapeutic intervention. Recent advances in medicinal chemistry have led to the development of small-molecule inhibitors, monoclonal antibodies, and bispecific antibodies that selectively modulate CD28 and ICOS signaling. This review examines the structural and functional properties of CD28 and ICOS, highlighting their ligand-binding domains, intracellular signaling motifs, and structure-activity relationships (SARs) relevant to drug discovery. Key therapeutic approaches include CTLA-4-Ig fusion proteins (abatacept, belatacept) for autoimmune diseases, ICOS agonists (feladilimab, vopratelimab) to enhance anti-tumor immunity, and bispecific CD28-engaging antibodies (CD28xCD3, CD28xPSMA) for cancer immunotherapy. Additionally, novel high-throughput screening (HTS) strategies, computational drug design, and rational engineering of antibody-based therapies are improving selectivity and minimizing immune-related toxicities. By integrating structural insights with translational drug development, this review provides a framework for optimizing CD28- and ICOS-targeted therapies. Further advancements in biologics, peptide-based inhibitors, and immune checkpoint modulation will enhance the precision and efficacy of immunotherapeutic strategies.