Targeting VISTA for immunomodulation in sepsis: mechanisms and therapeutic potentials

Sepsis is a life-threatening clinical syndrome defined as acute organ dysfunction caused by a dysregulated host response to infection. At the core of its pathophysiology lies the aberrant activation and dysregulation of the host immune system. The V-domain Ig suppressor of T cell activation (VISTA) is a dual-function immune checkpoint molecule that acts as both a receptor and a ligand, and exerts a pivotal immunoregulatory role in the pathological process of sepsis. Emerging preclinical and clinical evidence indicates that VISTA exerts stage-specific biphasic effects during the progression of sepsis. In the early hyperinflammatory phase, VISTA signaling potentially alleviates the cytokine storm and preserves the integrity of organ barriers; in contrast, during the subsequent immunosuppressive (immune paralysis) phase, aberrant VISTA upregulation may drive the sustained hyporesponsiveness of T cells and the tolerogenic reprogramming of myeloid cells. In this review, we systematically summarize and critically appraise the dynamic expression profiles of VISTA across different stages of sepsis, and synthesize current evidence regarding the multifaceted mechanisms by which VISTA modulates both excessive inflammatory responses and immunosuppression. We further evaluate preclinical studies investigating VISTA-targeted interventions, with a focus on their impacts on survival outcomes, organ injury, and immune cell function. Collectively, this review highlights the central regulatory role of VISTA in the immunoregulatory network of sepsis, and proposes that precision immunomodulatory strategies targeting VISTA hold significant promise as a novel therapeutic approach for patients with sepsis.