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Single-cell transcriptomic analysis reveals gut microbiota-immunotherapy synergy through modulating tumor microenvironment

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机构: [1]Department of Laboratory Medicine/Research Centre of Clinical Laboratory Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China. [2]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China. [3]Department of Clinical Pharmacology, Xiangya Hospital, Central Laboratory of Hunan Cancer Hospital, Central South University, Changsha, China. [4]Division of Gastrointestinal Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China. [5]Colorectal Cancer Center, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China. [6]Gastric Cancer Center, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China. [7]Core Facilities, West China Hospital, Sichuan University, Chengdu, China. [8]Department of Cardiology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China. [9]Center for Precision Medicine, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou, China. [10]The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China. [11]Lung Cancer Center/Lung Cancer Institute, Department of Medical Oncology, West China Hospital, Sichuan University, Chengdu, China. [12]Institute of General Surgery, West China Hospital, Sichuan University, Chengdu, China [13]Tianfu Jincheng Laboratory, Chengdu, China.
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The gut microbiota crucially regulates the efficacy of immune checkpoint inhibitor (ICI) based immunotherapy, but the underlying mechanisms remain unclear at the single-cell resolution. Using single-cell RNA sequencing and subsequent validations, we investigate gut microbiota-ICI synergy by profiling the tumor microenvironment (TME) and elucidating critical cellular interactions in mouse models. Our findings reveal that intact gut microbiota combined with ICIs may synergistically increase the proportions of CD8+, CD4+, and γδ T cells, reduce glycolysis metabolism, and reverse exhausted CD8+ T cells into memory/effector CD8+ T cells, enhancing antitumor response. This synergistic effect also induces macrophage reprogramming from M2 protumor Spp1+ tumor-associated macrophages (TAMs) to Cd74+ TAMs, which act as antigen-presenting cells (APCs). These macrophage subtypes show a negative correlation within tumors, particularly during fecal microbiota transplantation. Depleting Spp1+ TAMs in Spp1 conditional knockout mice boosts ICI efficacy and T cell infiltration, regardless of gut microbiota status, suggesting a potential upstream role of the gut microbiota and highlighting the crucial negative impact of Spp1+ TAMs during macrophage reprogramming on immunotherapy outcomes. Mechanistically, we propose a γδ T cell-APC-CD8+ T cell axis, where gut microbiota and ICIs enhance Cd40lg expression on γδ T cells, activating Cd40 overexpressing APCs (e.g., Cd74+ TAMs) through CD40-CD40L-related NF-κB signaling and boosting CD8+ T cell responses via CD86-CD28 interactions. These findings highlight the potential importance of γδ T cells and SPP1-related macrophage reprogramming in activating CD8+ T cells, as well as the synergistic effect of gut microbiota and ICIs in immunotherapy through modulating the TME.© 2025. The Author(s).

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大类 | 1 区 医学
小类 | 1 区 生化与分子生物学 1 区 细胞生物学
最新[2025]版:
大类 | 1 区 医学
小类 | 1 区 生化与分子生物学 1 区 细胞生物学
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第一作者机构: [1]Department of Laboratory Medicine/Research Centre of Clinical Laboratory Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China. [2]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
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通讯机构: [1]Department of Laboratory Medicine/Research Centre of Clinical Laboratory Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China. [2]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China. [3]Department of Clinical Pharmacology, Xiangya Hospital, Central Laboratory of Hunan Cancer Hospital, Central South University, Changsha, China. [10]The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China. [12]Institute of General Surgery, West China Hospital, Sichuan University, Chengdu, China [13]Tianfu Jincheng Laboratory, Chengdu, China.
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