V-domain immunoglobulin suppressor of T-cell activation (VISTA) immune checkpoint: a medicinal chemistry perspective

V-domain immunoglobulin suppressor of T-cell activation (VISTA) is an emerging immune checkpoint with distinctive structural and functional features distinct from PD-1/PD-L1 and CTLA-4. Constitutively expressed on naïve T cells and myeloid cells, VISTA functions as a master regulator of immune quiescence while being co-opted by tumors for immune evasion. VISTA engages multiple ligands, including PSGL-1, VSIG-3, VSIG-8, and LRIG-1, to suppress T-cell responses and mediate immunosuppression, thereby contributing to resistance to PD-1/PD-L1 blockade. Consequently, VISTA has emerged as a promising target for cancer immunotherapy. However, first-generation pH-independent antibodies encountered cytokine release syndrome and rapid clearance, spurring the development of pH-selective, Fc-engineered, and non-depleting antibody strategies. Concurrently, small-molecule VISTA inhibitors have advanced from controversial compounds to validated chemical matter across multiple scaffolds, with representative candidates demonstrating oral bioavailability, antitumor efficacy, and synergy with anti-PD-L1. Nevertheless, most small-molecule inhibitors remain preclinical, and a critical bottleneck persists. All reported small-molecule binding poses for VISTA are derived from molecular docking and require experimental validation by mutagenesis or co-crystallization. The absence of co-crystal structures continues to limit structure-based optimization. Here, we review VISTA biology from a medicinal chemistry perspective, covering its unique structural features, ligand interactions, and the landscape of antibody and small-molecule inhibitors. Finally, we discuss current challenges and future opportunities, with the aim of guiding the discovery of next-generation VISTA-targeted therapeutics for cancer immunotherapy and autoimmune diseases.