VISTA promotes ovarian cancer progression through activation of NF-κB pathway and tumor microenvironment reprogramming.

BACKGROUND: V-domain immunoglobulin suppressor of T-cell activation (VISTA), an immune checkpoint protein, is overexpressed in multiple cancers. However, its mechanistic role in ovarian cancer (OC) remains largely undefined. METHOD: Transcriptomic analysis of OC cohorts (OCA and OCB) and single-cell RNA sequencing (GSE184880) were conducted to evaluate VISTA expression and associated pathway enrichment. Functional assays, including proliferation, migration, and epithelial-mesenchymal transition (EMT) analyses, along with in vivo models, were employed to determine the role of VISTA in OC progression. Mechanistic investigations, incorporating co-immunoprecipitation (Co-IP), cycloheximide (CHX) chase, and dual-luciferase reporter assays, elucidated VISTA-mediated NF-κB activation. Immune profiling using CIBERSORT and flow cytometry was performed to characterize tumor microenvironment (TME) modulation. RESULT: VISTA was significantly upregulated in OC tissues and associated with poor prognosis. Furthermore, VISTA promoted OC cell proliferation, migration, EMT, and cell cycle progression. Mechanistically, VISTA bound HSP90AB1 to stabilize the VISTA/HSP90AB1/IKK complex, facilitating IKKα/β phosphorylation, p65 nuclear translocation to active NF-κB pathway. In vivo VISTA knockdown suppressed tumor growth, whereas its overexpression accelerated tumor progression. Notably, VISTAhigh OC exhibited reduced CD8 + T cell infiltration and dendritic cell activation, fostering an immunosuppressive TME. Depleting CD8 + T cells depletion abrogated the anti-tumor effects of VISTA inhibition. CONCLUSIONS: VISTA promotes OC progression through dual mechanisms: activation of the NF-κB pathway and immunosuppression within the tumor microenvironment. Targeting the VISTA/HSP90AB1/NF-κB axis represents a promising therapeutic strategy to counteract OC immune evasion and tumor aggressiveness.