Targeting VISTA as a novel immunotherapy for skin cancer.

While immune checkpoint blockade (ICB) targeting PD-1 and CTLA-4 has revolutionized the treatment of skin cancers, a significant proportion of patients with advanced melanoma and cutaneous squamous cell carcinoma (cSCC) exhibit primary or acquired resistance. Identifying non-redundant inhibitory pathways is crucial for the next generation of immunotherapy. As a unique checkpoint, VISTA (PD-1H) maintains immune tolerance through a distinct pH-sensitive mechanism. In the acidic tumor microenvironment (TME), protonated histidine residues enhance VISTA's binding affinity, allowing it to act as a localized guardian of immune privilege in both melanoma and cutaneous squamous cell carcinoma. By integrating molecular insights with bioengineering innovations, VISTA-directed rational combinations demonstrate significant preclinical potential to overcome immune resistance and achieve durable responses in refractory malignancies.