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SIRT1-CX3CL1轴介导的代谢性免疫抑制诱导结直肠癌中调节性T细胞功能增强

Metabolic-Immune Suppression Mediated by the SIRT1-CX3CL1 Axis Induces Functional Enhancement of Regulatory T Cells in Colorectal Carcinoma.

作者信息

Zi Ruiyang, Zhao Xiang, Liu Limei, Wang Yijie, Zhang Rui, Bian Zhiheng, Jiang Haoran, Liu Taorui, Sun Yixin, Peng Han, Wang Xuesong, Lu Fanghao, Zhang Chao, Zhang Fan, Qin Qing, Liang Houjie, Li Jianjun, Wei Zhihao, Dong Yan

机构信息

Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.

Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Cancer Hospital, Chongqing University, Chongqing, 400038, China.

出版信息

Adv Sci (Weinh). 2025 May;12(17):e2404734. doi: 10.1002/advs.202404734. Epub 2025 Jan 9.

DOI:10.1002/advs.202404734
PMID:39783838
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12061293/
Abstract

Metabolic reprogramming of tumor cells dynamically reshapes the distribution of nutrients and signals in the tumor microenvironment (TME), affecting intercellular interactions and resulting in metabolic immune suppression. Increased glucose uptake and metabolism are characteristic of many tumors. Meanwhile, the progression of colorectal carcinoma (CRC) relies on lipid metabolism. Therefore, investigating the role of glucolipid metabolic reprogramming on tumor immunity contributes to identifying new targets for immune suppression intervention in CRC. Our previous work demonstrated that SIRT1 is the hub gene involved in glucolipid metabolic conversion in CRC. Here, it is found that upregulated SIRT1 in CRC cells increases Treg functionality by promoting the secretion of CX3CL1. The CX3CL1-CX3CR1 signaling activated transcription factors SATB1 and BTG2, promoting the differentiation of TCF7 Treg cells into functionally enhanced TNFRSF9 Treg cells. Multiplex immunofluorescence (mIHC) analysis of a CRC tissue microarray confirmed the promoting effect of CX3CL1 on Treg infiltration. Additionally, the therapeutic efficacy of CX3CR1 inhibitor monotherapy and combination therapy is validated with the PD-1 antibody in the humanized subcutaneous CRC mouse model. This study elucidates a potential mechanism that metabolic reprogramming of cancer cells collaborates with subsequent immunosuppression to promote CRC progression.

摘要

肿瘤细胞的代谢重编程动态重塑肿瘤微环境（TME）中的营养物质和信号分布，影响细胞间相互作用并导致代谢性免疫抑制。葡萄糖摄取和代谢增加是许多肿瘤的特征。同时，结直肠癌（CRC）的进展依赖于脂质代谢。因此，研究糖脂代谢重编程在肿瘤免疫中的作用有助于确定CRC免疫抑制干预的新靶点。我们之前的工作表明，SIRT1是参与CRC糖脂代谢转换的枢纽基因。在此发现，CRC细胞中SIRT1的上调通过促进CX3CL1的分泌增加了调节性T细胞（Treg）的功能。CX3CL1-CX3CR1信号激活转录因子SATB1和BTG2，促进TCF7 Treg细胞分化为功能增强的TNFRSF9 Treg细胞。对CRC组织微阵列的多重免疫荧光（mIHC）分析证实了CX3CL1对Treg浸润的促进作用。此外，在人源化皮下CRC小鼠模型中用PD-1抗体验证了CX3CR1抑制剂单药治疗和联合治疗的疗效。本研究阐明了一种潜在机制，即癌细胞的代谢重编程与随后的免疫抑制协同作用以促进CRC进展。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e8a7/12061293/1e5e3d713b04/ADVS-12-2404734-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e8a7/12061293/fb7a06b69363/ADVS-12-2404734-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e8a7/12061293/57c8da4e5307/ADVS-12-2404734-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e8a7/12061293/5ccf300a32bf/ADVS-12-2404734-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e8a7/12061293/af288d6afaaa/ADVS-12-2404734-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e8a7/12061293/5c47284e1642/ADVS-12-2404734-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e8a7/12061293/1e5e3d713b04/ADVS-12-2404734-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e8a7/12061293/fb7a06b69363/ADVS-12-2404734-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e8a7/12061293/57c8da4e5307/ADVS-12-2404734-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e8a7/12061293/5ccf300a32bf/ADVS-12-2404734-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e8a7/12061293/af288d6afaaa/ADVS-12-2404734-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e8a7/12061293/5c47284e1642/ADVS-12-2404734-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e8a7/12061293/1e5e3d713b04/ADVS-12-2404734-g001.jpg

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