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Background <p>Chimeric antigen receptor (CAR)-T cell therapy faces significant challenges in treating solid tumors, primarily due to the immunosuppressive tumor microenvironment (TME) and rapid T-cell exhaustion mediated by cytokines such as transforming growth factor-β (TGF-β). Developing strategies to remodel the TME and sustain T-cell function is critical. In this study, we investigated a pharmacological strategy using Asiaticoside (AC), a natural compound, as an adjuvant to enhance the efficacy of mesothelin (MSLN)-targeting CAR-T cells in ovarian cancer.</p> Methods <p>We engineered MSLN-specific CAR-T cells and evaluated their therapeutic efficacy in combination with AC using in vitro co-culture assays and in vivo xenograft models. Transcriptional changes were analyzed via RNA sequencing (RNA-seq), while the underlying molecular mechanism was investigated by focusing on the TGF-β/SMAD signaling axis. In vivo efficacy and safety were evaluated in NCG mice bearing subcutaneous or intraperitoneal metastatic SKOV-3-luc ovarian tumors, treated with the combination of CAR-T cells and AC.</p> Results <p>AC treatment significantly potentiated CAR-T cell cytotoxicity and reduced the expression of exhaustion markers (PD-1, TIM-3, and LAG-3) upon continuous antigen exposure. Mechanistically, AC functioned as an inhibitor of TGF-β signaling, effectively suppressing TGF-β1-induced phosphorylation of SMAD2/3. In mouse models, the combination of AC and CAR-T therapy exerted superior antitumor activity compared to CAR-T monotherapy, significantly suppressing tumor growth without inducing systemic toxicity or organ damage.</p> Conclusion <p>Our findings demonstrate that AC alleviates CAR-T cell exhaustion and antagonizes TGF-β-mediated immunosuppression. AC represents a promising, clinically translatable pharmacological adjuvant to overcome the bottlenecks of CAR-T cell therapy in solid tumors.</p>

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Asiaticoside enhances the antitumor efficacy of MSLN-targeted CAR-T cells in ovarian cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月26日

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  • Wei Jiang,
  • Juanwen Cao,
  • Qi Li,
  • Yuyan Xie,
  • Xiaoying Li,
  • Xifeng Pan,
  • Miaomiao Yu,
  • Dan Zou,
  • Bonan Sun,
  • Wei Yang,
  • Xiaoyi Huang,
  • Yu Tang

摘要

Background

Chimeric antigen receptor (CAR)-T cell therapy faces significant challenges in treating solid tumors, primarily due to the immunosuppressive tumor microenvironment (TME) and rapid T-cell exhaustion mediated by cytokines such as transforming growth factor-β (TGF-β). Developing strategies to remodel the TME and sustain T-cell function is critical. In this study, we investigated a pharmacological strategy using Asiaticoside (AC), a natural compound, as an adjuvant to enhance the efficacy of mesothelin (MSLN)-targeting CAR-T cells in ovarian cancer.

Methods

We engineered MSLN-specific CAR-T cells and evaluated their therapeutic efficacy in combination with AC using in vitro co-culture assays and in vivo xenograft models. Transcriptional changes were analyzed via RNA sequencing (RNA-seq), while the underlying molecular mechanism was investigated by focusing on the TGF-β/SMAD signaling axis. In vivo efficacy and safety were evaluated in NCG mice bearing subcutaneous or intraperitoneal metastatic SKOV-3-luc ovarian tumors, treated with the combination of CAR-T cells and AC.

Results

AC treatment significantly potentiated CAR-T cell cytotoxicity and reduced the expression of exhaustion markers (PD-1, TIM-3, and LAG-3) upon continuous antigen exposure. Mechanistically, AC functioned as an inhibitor of TGF-β signaling, effectively suppressing TGF-β1-induced phosphorylation of SMAD2/3. In mouse models, the combination of AC and CAR-T therapy exerted superior antitumor activity compared to CAR-T monotherapy, significantly suppressing tumor growth without inducing systemic toxicity or organ damage.

Conclusion

Our findings demonstrate that AC alleviates CAR-T cell exhaustion and antagonizes TGF-β-mediated immunosuppression. AC represents a promising, clinically translatable pharmacological adjuvant to overcome the bottlenecks of CAR-T cell therapy in solid tumors.