VISTA as a Double-Edged immune checkpoint molecule in cancer and autoimmunity.

V-domain Ig suppressor of T-cell activation (VISTA) is an emerging immune checkpoint molecule with a multifaceted role in regulating immune responses, presenting a "double-edged sword" in therapeutic contexts. While current immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 and CTLA-4 have revolutionized cancer immunotherapy, their efficacy is limited by primary and acquired resistance. VISTA, expressed predominantly on myeloid cells and T cells, acts as a crucial regulator of T-cell quiescence and peripheral tolerance, distinguishing it from conventional checkpoints. Structurally unique within the B7 family, VISTA functions as both an inhibitory ligand and receptor, engaging multiple binding partners like VSIG-3 and PSGL-1 to suppress T-cell activation and promote an immunosuppressive tumor microenvironment. Its elevated expression in various cancers, often linked to ICI resistance, positions VISTA as a promising target to enhance anti-tumor immunity. Preclinical studies demonstrate that VISTA blockade can improve antigen presentation and synergize with existing ICIs. Conversely, VISTA's role in maintaining peripheral tolerance highlights its potential as a therapeutic target in autoimmune diseases. This dual capacity underscores VISTA's critical balance between immune activation and tolerance, making it a pivotal target for precision immunomodulation in both oncology and autoimmune disorders.