Niu Xiangyun, Zhang Pengchao, Liu Zhongming, Tang Yexiao, Xu Shu, Wan Xiaochun, Xu Zhiming, Zhang Guizhong
Guangdong 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, China.
University of Chinese Academy of Sciences, Beijing, China.
Front Immunol. 2025 Jul 18;16:1605488. doi: 10.3389/fimmu.2025.1605488. eCollection 2025.
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 , potently enhances CAR-T cell function against solid tumors. , 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 CD44CD62L central memory cells and enrichment of CD44CD62LTCF1 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 (encoding TCF1) and . , 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.
嵌合抗原受体（CAR）T细胞疗法在治疗血液系统恶性肿瘤方面已取得显著成功；然而，其在实体瘤中的疗效仍然受限。在本研究中，我们证明了香菇多糖（LTN），一种从[来源未提及]中提取的活性多糖，能有效增强CAR-T细胞针对实体瘤的功能。具体而言，LTN显著增强了CAR-T细胞的细胞毒性和促炎细胞因子分泌（白细胞介素-2、干扰素-γ）。从机制上讲，LTN促使CAR-T细胞分化为记忆表型，其特征是CD44⁺CD62L⁺中央记忆细胞频率增加以及CD44⁺CD62L⁺TCF1⁺干细胞样记忆细胞富集，同时减轻耗竭，这表现为检查点受体TIM-3和耗竭相关标志物CD317的表面表达降低。这些表型和功能的改善与LTN介导的记忆相关因子（编码TCF1）和[未提及具体因子]的转录上调相关。此外，LTN与CAR-T的联合显著增强了同基因小鼠结肠癌和黑色素瘤模型中的肿瘤控制。这种卓越的疗效源于增强的CAR-T细胞持久性、持续的肿瘤内效应功能以及肿瘤相关巨噬细胞（TAM）向免疫刺激的M1样表型的重编程。这项工作确立了LTN作为一种具有临床可操作性的免疫调节剂，它通过内在增强CAR-T细胞的适应性和持久性，同时外在重塑抑制性肿瘤微环境，与CAR-T细胞协同作用。它提供了一种新的、可转化的策略来增强CAR-T细胞疗法对实体瘤的治疗效果。
