VISTA+ neutrophils contribute to platinum resistance by suppressing CD8+T cells in high-grade serous ovarian cancer

Elevated neutrophil-to-lymphocyte ratio (NLR) has been associated with platinum resistance and poor outcomes in high-grade serous ovarian cancer (HGSOC), but the biological basis of this association remains unclear. We retrospectively analyzed 434 patients with HGSOC treated with platinum-based chemotherapy and found that elevated NLR was an independent predictor of platinum resistance. To further investigate the cellular basis of this association, we performed immunohistochemistry, proteomic profiling, and single-cell RNA sequencing on patient samples. These analyses identified a distinct subpopulation of V-domain immunoglobulin suppressor of T cell activation-positive neutrophils (VISTA⁺Neus) enriched in resistant tumors. High VISTA⁺Neus density was linked to shorter progression-free survival and showed greater predictive value for resistance than total neutrophils. Spatial and multicolor immunohistochemistry analyses further showed that VISTA⁺Neus were associated with reduced CD8⁺T-cell infiltration and cytotoxic features. Functional validation in an immunocompetent mouse model showed that anti-VISTA plus cisplatin reduced tumor growth, decreased neutrophil abundance, and increased CD8⁺T-cell infiltration and granzyme B expression. CD8⁺ T-cell depletion markedly attenuated the therapeutic benefit of the combination. These findings support VISTA⁺Neus as a potential immunosuppressive neutrophil subset associated with platinum resistance and CD8⁺T-cell suppression in HGSOC, and support further investigation of VISTA-targeted strategies and the potential biomarker value of VISTA⁺Neus.