Combined targeting of VISTA and sorafenib activates T cell-mediated anti-tumor immunity via the NF-κB/TNF axis in hepatocellular carcinoma

BACKGROUND: Hepatocellular carcinoma (HCC) is a highly aggressive malignancy, with most patients diagnosed at advanced stages. Sorafenib, a multi-targeted tyrosine kinase inhibitor, remains a first-line therapy but has limited efficacy as monotherapy. Combining sorafenib with immune checkpoint inhibitors has become a leading strategy for unresectable advanced HCC. However, intrinsic and acquired resistance, together with immune-related adverse events, limit clinical benefit to a subset of patients, highlighting the need for new immunotherapeutic targets. V-domain Ig suppressor of T cell activation (VISTA), an emerging immune checkpoint molecule, is overexpressed in multiple cancers and associated with prognosis, suggesting its therapeutic potential in HCC. METHODS: VISTA expression and its association with T-cell infiltration were evaluated in human HCC tissues. An in vitro co-culture system and an orthotopic HCC model in C57BL/6 mice were used to assess the antitumor efficacy of anti-VISTA antibody and sorafenib, alone or in combination. Sequential and concurrent regimens were further compared. The efficacy of combination therapy relative to monotherapy was validated in a patient-derived xenograft (PDX) model in NCG mice with adoptive T cell transfer. Transcriptomic sequencing and functional rescue experiments were performed to investigate the underlying mechanisms. RESULTS: VISTA was significantly overexpressed in HCC tissues and positively correlated with T cell infiltration. In the C57BL/6 orthotopic model, only the combination regimen significantly inhibited tumor growth compared with control treatment, whereas neither monotherapy reached statistical significance. Combination therapy enhanced T cell infiltration and cytotoxic function compared with monotherapy. Notably, only concurrent administration significantly suppressed tumor growth, whereas both sequential regimens showed nonsignificant inhibitory trends. In the NCG mouse PDX model, monotherapies produced moderate antitumor effects; the combination group showed significantly greater antitumor activity than anti-VISTA monotherapy and a numerical, but nonsignificant, advantage over sorafenib monotherapy. Transcriptomic profiling and functional rescue experiments implicated the NF-κB/TNF signaling pathway in this synergistic effect. CONCLUSIONS: Concurrent VISTA blockade plus sorafenib exerts synergistic antitumor effects in HCC, associated with enhanced T cell function and NF‑κB/TNF pathway modulation. Concurrent treatment showed stronger antitumor trends than sequential regimens. These findings support further exploration of VISTA‑targeted combination immunotherapy and provide insights into optimal regimen sequencing.