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Background <p>Despite advances in chimeric antigen receptor T-cell (CAR-T) therapy, significant challenges remain, including progressive T-cell exhaustion and poor in vivo persistence. Current strategies to enhance CAR-T function—such as cytokine co-expression—often lead to severe adverse effects, most notably cytokine release syndrome (CRS). Therefore, there is a pressing need to develop safer and more sustainable approaches, particularly through nutritional interventions, to improve the antitumor efficacy of CAR-T therapy. Fucoidan (FO), a bioactive polysaccharide derived from marine plants, has demonstrated immunomodulatory properties and synergistic potential in combination with conventional chemotherapy. However, its role in cellular immunotherapy, including CAR-T therapy, has not yet been explored. This study aims to elucidate the function of FO in CAR-T therapy for non-Hodgkin lymphoma (NHL) and to provide a foundational basis for its clinical translation in the field of cellular immunotherapy.</p> Methods <p>The current study used a combination of in vitro and in vivo assays to explore the role of FO in CAR T therapy. The anti-CD19 CAR-T cells were constructed by lentivirus containing CAR-CD19 structure. For phenotype analysis of CAR T cells, different cell populations, such as memory and exhausted CAR T cells, were stained by cell marker and identified by flow cytometry. CAR-T cells from different treatment groups were co-cultured with target cells with different E: T ratio to detect the cytotoxicity and cytokine release of CAR-T cells. We also evaluate FO’s supportive role for function of CAR-T cells in the tumor-bearing mouse models. The underlying mechanism of activated signaling pathway were also investigated and confirmed by the inhibitor.</p> Results <p>In this study, we systematically investigated the role of FO in anti-CD19 CAR-T cell-mediated treatment of NHL. Specifically, CAR-T cells’ memory maintenance and exhaustion resistance were enhanced by FO. FO not only improved CAR-T cell’s antioxidant capacity and proliferation, but also prevented apoptosis of activated CAR-T cells, collectively contributing to the improved and sustained anti-tumor efficacy in both in vitro assays and xenograft models. Our mechanistic studies also revealed FO served as a potentiator for CAR-T cells’ function through enhancing the activation of STAT3 signaling pathway.</p> Conclusions <p>These findings elucidate the supportive role of FO in enhancing CAR-T cell function, which indicates FO’s clinical potential as immunomodulatory supplement to potentiate CAR-T therapy against NHL.</p>

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Fucoidan potentiates anti-tumor efficacy of CAR-T cells against non-Hodgkin lymphoma by activation of STAT3 pathway

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月13日

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  • Qingzheng Kang,
  • Liang Zhang,
  • Xiaoqing Wu,
  • Xuanren Shi

摘要

Background

Despite advances in chimeric antigen receptor T-cell (CAR-T) therapy, significant challenges remain, including progressive T-cell exhaustion and poor in vivo persistence. Current strategies to enhance CAR-T function—such as cytokine co-expression—often lead to severe adverse effects, most notably cytokine release syndrome (CRS). Therefore, there is a pressing need to develop safer and more sustainable approaches, particularly through nutritional interventions, to improve the antitumor efficacy of CAR-T therapy. Fucoidan (FO), a bioactive polysaccharide derived from marine plants, has demonstrated immunomodulatory properties and synergistic potential in combination with conventional chemotherapy. However, its role in cellular immunotherapy, including CAR-T therapy, has not yet been explored. This study aims to elucidate the function of FO in CAR-T therapy for non-Hodgkin lymphoma (NHL) and to provide a foundational basis for its clinical translation in the field of cellular immunotherapy.

Methods

The current study used a combination of in vitro and in vivo assays to explore the role of FO in CAR T therapy. The anti-CD19 CAR-T cells were constructed by lentivirus containing CAR-CD19 structure. For phenotype analysis of CAR T cells, different cell populations, such as memory and exhausted CAR T cells, were stained by cell marker and identified by flow cytometry. CAR-T cells from different treatment groups were co-cultured with target cells with different E: T ratio to detect the cytotoxicity and cytokine release of CAR-T cells. We also evaluate FO’s supportive role for function of CAR-T cells in the tumor-bearing mouse models. The underlying mechanism of activated signaling pathway were also investigated and confirmed by the inhibitor.

Results

In this study, we systematically investigated the role of FO in anti-CD19 CAR-T cell-mediated treatment of NHL. Specifically, CAR-T cells’ memory maintenance and exhaustion resistance were enhanced by FO. FO not only improved CAR-T cell’s antioxidant capacity and proliferation, but also prevented apoptosis of activated CAR-T cells, collectively contributing to the improved and sustained anti-tumor efficacy in both in vitro assays and xenograft models. Our mechanistic studies also revealed FO served as a potentiator for CAR-T cells’ function through enhancing the activation of STAT3 signaling pathway.

Conclusions

These findings elucidate the supportive role of FO in enhancing CAR-T cell function, which indicates FO’s clinical potential as immunomodulatory supplement to potentiate CAR-T therapy against NHL.