VISTA as a context-dependent immune checkpoint: Implications for tumor immunity and autoimmune pathogenesis

Abstract

V-domain Ig suppressor of T cell activation (VISTA) is a recently characterized as immune checkpoint regulator with critical roles in modulating immune responses across pathological contexts. In cancer, VISTA contributes to immune evasion by sustaining an immunosuppressive tumor microenvironment, emerging as a promising target for immunotherapeutic intervention. In contrast, in autoimmune diseases, VISTA preserves peripheral immune tolerance and suppresses aberrant immune activation, thereby preventing tissue destruction. This functional dichotomy reflects the complexity of VISTA-mediated signaling, which is modulated by cellular context, microenvironmental cues, and disease stage. Recent studies have elucidated key aspects of VISTA biology, including its structural features, ligand interactions, and context-dependent expression patterns. VISTA operates as a co-inhibitory molecule in cancer, while exerting co-stimulatory or regulatory effects in autoimmunity. This review provides a comprehensive overview of VISTA's discovery, molecular mechanisms, and dual roles in cancer and autoimmune pathogenesis. Furthermore, the current status of VISTA-targeted therapeutic strategies is critically examined, highlighting the translational challenges posed by discrepancies between preclinical models and clinical trial outcomes. Finally, the potential of targeting VISTA within the broader paradigm of immune checkpoint plasticity is discussed, with emphasis on overcoming compensatory immune resistance to enhance therapeutic efficacy. A deeper mechanistic understanding of VISTA is essential for the rational design of future immunomodulatory therapies tailored to specific disease contexts.