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

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.