Lentinan enhances CAR-T cell potency in solid tumors by optimizing T cell differentiation
CAR-T cell therapy has demonstrated remarkable success in treating hematologic malignancies; however, its efficacy in solid tumors remains constrained. In this study, we demonstrate that Lentinan (LTN), an active polysaccharide derived from Lentinula edodes, potently enhances CAR-T cell function aga...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2025-07-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1605488/full |
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| author | Xiangyun Niu Xiangyun Niu Pengchao Zhang Pengchao Zhang Zhongming Liu Yexiao Tang Shu Xu Xiaochun Wan Xiaochun Wan Zhiming Xu Guizhong Zhang Guizhong Zhang |
| author_facet | Xiangyun Niu Xiangyun Niu Pengchao Zhang Pengchao Zhang Zhongming Liu Yexiao Tang Shu Xu Xiaochun Wan Xiaochun Wan Zhiming Xu Guizhong Zhang Guizhong Zhang |
| author_sort | Xiangyun Niu |
| collection | DOAJ |
| description | CAR-T cell therapy has demonstrated remarkable success in treating hematologic malignancies; however, its efficacy in solid tumors remains constrained. In this study, we demonstrate that Lentinan (LTN), an active polysaccharide derived from Lentinula edodes, potently enhances CAR-T cell function against solid tumors. In vitro, LTN significantly augments CAR-T cell cytotoxicity and pro-inflammatory cytokine secretion (IL-2, IFN-γ). Mechanistically, LTN drives CAR-T cell differentiation into a memory phenotype, characterized by increased frequencies of CD44+CD62L+ central memory cells and enrichment of CD44+CD62L+TCF1+ stem-like memory cells, while concomitantly mitigating exhaustion, as evidenced by reduced surface expression of the checkpoint receptor TIM-3 and the exhaustion-associated marker CD317. These phenotypic and functional improvements correlate with LTN-mediated transcriptional upregulation of memory-associated factors Tcf7 (encoding TCF1) and Foxo1. In vivo, the combination of LTN and CAR-T significantly enhances tumor control in syngeneic murine models of colon carcinoma and melanoma. This superior efficacy stems from enhanced CAR-T cell persistence, sustained intratumoral effector function, and reprogramming of tumor-associated macrophages (TAMs) toward an immunostimulatory M1-like phenotype. This work establishes LTN as a clinically actionable immunomodulator that synergizes with CAR-T cells by intrinsically enhancing their fitness and persistence while extrinsically remodeling the suppressive tumor microenvironment. It provides a novel, translatable strategy to potentiate CAR-T therapy against solid tumors. |
| format | Article |
| id | doaj-art-b2d9d312dc014ff48b73f6a2d24a873f |
| institution | Matheson Library |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-b2d9d312dc014ff48b73f6a2d24a873f2025-07-18T05:25:40ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-07-011610.3389/fimmu.2025.16054881605488Lentinan enhances CAR-T cell potency in solid tumors by optimizing T cell differentiationXiangyun Niu0Xiangyun Niu1Pengchao Zhang2Pengchao Zhang3Zhongming Liu4Yexiao Tang5Shu Xu6Xiaochun Wan7Xiaochun Wan8Zhiming Xu9Guizhong Zhang10Guizhong Zhang11Guangdong Immune Cell Therapy Engineering and Technology Research Center, Center for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, ChinaUniversity of Chinese Academy of Sciences, Beijing, ChinaGuangdong Immune Cell Therapy Engineering and Technology Research Center, Center for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, ChinaUniversity of Chinese Academy of Sciences, Beijing, ChinaGuangdong Immune Cell Therapy Engineering and Technology Research Center, Center for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, ChinaCancer Center, Shenzhen Guangming District People’s Hospital, Shenzhen, ChinaCancer Center, Shenzhen Guangming District People’s Hospital, Shenzhen, ChinaGuangdong Immune Cell Therapy Engineering and Technology Research Center, Center for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, ChinaUniversity of Chinese Academy of Sciences, Beijing, ChinaCancer Center, Shenzhen Guangming District People’s Hospital, Shenzhen, ChinaGuangdong Immune Cell Therapy Engineering and Technology Research Center, Center for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, ChinaUniversity of Chinese Academy of Sciences, Beijing, ChinaCAR-T cell therapy has demonstrated remarkable success in treating hematologic malignancies; however, its efficacy in solid tumors remains constrained. In this study, we demonstrate that Lentinan (LTN), an active polysaccharide derived from Lentinula edodes, potently enhances CAR-T cell function against solid tumors. In vitro, LTN significantly augments CAR-T cell cytotoxicity and pro-inflammatory cytokine secretion (IL-2, IFN-γ). Mechanistically, LTN drives CAR-T cell differentiation into a memory phenotype, characterized by increased frequencies of CD44+CD62L+ central memory cells and enrichment of CD44+CD62L+TCF1+ stem-like memory cells, while concomitantly mitigating exhaustion, as evidenced by reduced surface expression of the checkpoint receptor TIM-3 and the exhaustion-associated marker CD317. These phenotypic and functional improvements correlate with LTN-mediated transcriptional upregulation of memory-associated factors Tcf7 (encoding TCF1) and Foxo1. In vivo, the combination of LTN and CAR-T significantly enhances tumor control in syngeneic murine models of colon carcinoma and melanoma. This superior efficacy stems from enhanced CAR-T cell persistence, sustained intratumoral effector function, and reprogramming of tumor-associated macrophages (TAMs) toward an immunostimulatory M1-like phenotype. This work establishes LTN as a clinically actionable immunomodulator that synergizes with CAR-T cells by intrinsically enhancing their fitness and persistence while extrinsically remodeling the suppressive tumor microenvironment. It provides a novel, translatable strategy to potentiate CAR-T therapy against solid tumors.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1605488/fullCAR-T cell therapylentinancentral memory T cellssolid tumortumor microenvironment |
| spellingShingle | Xiangyun Niu Xiangyun Niu Pengchao Zhang Pengchao Zhang Zhongming Liu Yexiao Tang Shu Xu Xiaochun Wan Xiaochun Wan Zhiming Xu Guizhong Zhang Guizhong Zhang Lentinan enhances CAR-T cell potency in solid tumors by optimizing T cell differentiation Frontiers in Immunology CAR-T cell therapy lentinan central memory T cells solid tumor tumor microenvironment |
| title | Lentinan enhances CAR-T cell potency in solid tumors by optimizing T cell differentiation |
| title_full | Lentinan enhances CAR-T cell potency in solid tumors by optimizing T cell differentiation |
| title_fullStr | Lentinan enhances CAR-T cell potency in solid tumors by optimizing T cell differentiation |
| title_full_unstemmed | Lentinan enhances CAR-T cell potency in solid tumors by optimizing T cell differentiation |
| title_short | Lentinan enhances CAR-T cell potency in solid tumors by optimizing T cell differentiation |
| title_sort | lentinan enhances car t cell potency in solid tumors by optimizing t cell differentiation |
| topic | CAR-T cell therapy lentinan central memory T cells solid tumor tumor microenvironment |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1605488/full |
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