Lentinan enhances CAR-T cell potency in solid tumors by optimizing T cell differentiation

Xiangyun Niu^1,2Pengchao Zhang^1,2Zhongming Liu¹Yexiao Tang³Shu Xu³Xiaochun Wan¹Zhiming Xu³Guizhong Zhang^1*

• ¹Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences (CAS), Shenzhen, Guangdong Province, China
• ²University of Chinese Academy of Sciences, Beijing, Beijing, China
• ³Shenzhen Guangming District People's Hospital, Shenzhen, China

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 proinflammatory 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 reprogramming: upregulation of memoryassociated 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.