双特异性磷酸酶 4 通过抑制肝细胞癌中 TGF-β1 分泌增强免疫治疗应答

Background : Tumor immune microenvironment (TIME) heterogeneity limits immunotherapy efficacy in hepatocellular carcinoma (HCC), underscoring the need for predictive biomarkers and therapeutic targets.

We previously identified dual specificity phosphatase 4 (DUSP4) as a mediator of sorafenib resistance, but its immunomodulatory role remains unknown. Methods : Glypican-3 (GPC3)-specific chimeric antigen receptor (CAR) T-cell cytotoxicity assays were performed to assess the impact of DUSP4 on HCC immune susceptibility. A subcutaneous tumor model using Dusp4-overexpressing cells in female C57BL/6J mice was established to evaluate DUSP4-mediated microenvironment remodeling and anti-PD-L1 therapy efficacy.

Bulk RNA sequencing of DUSP4-overexpressing HCC cells identified downstream pathways. Public datasets were interrogated to correlate DUSP4 expression with immune checkpoint blockade (ICB) response and immune infiltration in HCC. Results : DUSP4 overexpression significantly enhanced HCC cell susceptibility to CAR-T cell killing in vitro and potentiated anti-PD-L1 efficacy in vivo, accompanied by TIME remodeling.

Mechanistically, RNA sequencing revealed DUSP4-mediated downregulation of the TGF- signaling pathway, functionally confirmed using a neutralizing antibody that abrogated the enhanced CAR-T killing. Public datasets confirmed associations between DUSP4 expression and enhanced immune cytolytic activity with favorable prognostic outcomes in HCC.

Conclusions : DUSP4 serves as a critical molecular nexus linking targeted therapy resistance to enhanced immunotherapy sensitivity. By attenuating the TGF- signaling pathway, DUSP4 reprograms TIME toward an immunologically active state, thereby augmenting the efficacy of immunotherapy.

These findings establish DUSP4 as a promising dynamic biomarker for guiding sequential therapy in HCC and highlight its potential as a novel therapeutic target to improve outcomes in solid tumor immunotherapy.