Dual Specificity Phosphatase 4 Enhances Immunotherapy Response by Inhibiting TGF-β1 Secretion in Hepatocellular Carcinoma.

Simple Summary: Hepatocellular carcinoma (HCC) remains a challenging malignancy with limited response to immunotherapy. Although immune checkpoint blockade has shown promising results, its efficacy is often compromised in clinical practice due to the immunosuppressive tumor microenvironment. In this study, we investigated the molecular mechanisms underlying immune resistance and identified DUSP4 as a candidate modulator of this process. Our results demonstrate that elevated DUSP4 levels enhance tumor cell susceptibility to T-cell-mediated killing by suppressing TGF-β1 secretion. Importantly, upregulated DUSP4 expression significantly improves immunotherapy efficacy in both mouse models and patient data analyses. These findings reveal a previously unrecognized mechanism regulating the tumor immune microenvironment and suggest that targeting the DUSP4/TGF-β1 axis could improve outcomes for patients with HCC. 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-β 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-β 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. [ABSTRACT FROM AUTHOR]

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