Structural Foundation of CTLA-4 antibodies: Emerging Platforms for Next-generation Cancer Immunotherapy.

Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is a critical immune checkpoint receptor that restrains T-cell activation and maintains peripheral tolerance by outcompeting CD28 for shared B7 ligands on antigen-presenting cells (APC). Dysregulation of CTLA-4 signaling is implicated in autoimmune pathologies, lymphoproliferative disorders, and tumor immune evasion, underscoring its broad therapeutic relevance. As the first checkpoint target validated in cancer immunotherapy, CTLA-4 has been extensively characterized at the structural level. High-resolution crystallographic studies have revealed how its extracellular IgV-like domain, MYPPPY ligand-binding motif, and cytoplasmic trafficking machinery collectively encode inhibitory function. Therapeutic antibodies targeting CTLA-4, including the FDA-approved agents ipilimumab and tremelimumab, achieve checkpoint blockade through steric occlusion of the B7-binding interface, inhibition of transendocytosis, and Fc-mediated regulatory T-cell depletion. Despite shared mechanisms, these agents differ markedly in effector function and toxicity profile. Other antibodies, including JS007, have entered clinical evaluation, while structurally characterized agents such as mipi.4 and KN044 provide preclinical and translational insights. Emerging engineering strategies, Fc-optimized variants, tumor-activated prodrug formats, bispecific antibodies, and alternative scaffolds such as nanobodies and DARPins are now translating these structural insights into next-generation therapeutics with improved selectivity and reduced immune-related adverse events. By connecting atomic-level receptor recognition to clinical outcome, this review provides a mechanistic foundation for the rational design of next-generation CTLA-4 therapeutics with improved efficacy and reduced immune-related toxicity.