CD28 is a critical T cell costimulatory molecule that functions as a transmembrane signaling receptor essential for adaptive immunity. Structurally, CD28 provides the second signal required alongside T cell receptor (TCR) ligation for naive T cell activation 1. Mechanistically, CD28 engages with B7 ligands (B7.1 and B7.2) and activates multiple signaling cascades including phosphoinositide 3-kinase, phospholipase C, and p21ran, leading to cyclosporin A-resistant signals distinct from TCR signaling 2. CD28 ligation promotes cytoskeletal remodeling, cytokine production (IL-2, IL-4, IL-10), T cell proliferation, survival, and regulatory T cell differentiation and maintenance 1. Functionally, CD28 signaling is critical for regulatory T cell development in the thymus and peripheral immune homeostasis 3. Disease relevance includes Immunodeficiency 123 with HPV-related verrucosis, while CD28 loss correlates with T cell senescence in aging and chr2 infections 4. Notably, a non-classical cancer cell-intrinsic CD28 function promotes immune escape by stabilizing PD-L1 mRNA, and targeting this pathway enhances anti-PD-1 immunotherapy efficacy 5. Clinically, CD28 costimulatory domains are incorporated into chimeric antigen receptor (CAR) T cell therapies to enhance anti-tumor cytotoxicity and proliferation 67.