Spatially resolved C1QC+ macrophage-CD4+ T cell niche in colorectal cancer microenvironment: implications for immunotherapy response
Abstract Colorectal cancer (CRC), including both microsatellite instability (MSI) and microsatellite stability (MSS) subtypes, frequently exhibits intrinsic resistance to immunotherapy. However, the spatial tumor microenvironment (TME) and its role in distinguishing immunotherapy responders from non...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-07-01
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| Series: | Cell Discovery |
| Online Access: | https://doi.org/10.1038/s41421-025-00811-2 |
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| author | Hangyu Zhang Libing Hong Zhen Dong Shan Xin Bo Lin Jinlin Cheng Weihong Tian Bin Li Jing Wang Xiaoyan Liu Chuan Liu Yuzhi Jin Yanzhi Feng Ge Su Xuqi Sun Qiqi Liu Xiaomeng Dai Yang Gao Zhou Tong Lulu Liu Xudong Zhu Yi Zheng Peng Zhao Tiannan Guo Weijia Fang Xuanwen Bao |
| author_facet | Hangyu Zhang Libing Hong Zhen Dong Shan Xin Bo Lin Jinlin Cheng Weihong Tian Bin Li Jing Wang Xiaoyan Liu Chuan Liu Yuzhi Jin Yanzhi Feng Ge Su Xuqi Sun Qiqi Liu Xiaomeng Dai Yang Gao Zhou Tong Lulu Liu Xudong Zhu Yi Zheng Peng Zhao Tiannan Guo Weijia Fang Xuanwen Bao |
| author_sort | Hangyu Zhang |
| collection | DOAJ |
| description | Abstract Colorectal cancer (CRC), including both microsatellite instability (MSI) and microsatellite stability (MSS) subtypes, frequently exhibits intrinsic resistance to immunotherapy. However, the spatial tumor microenvironment (TME) and its role in distinguishing immunotherapy responders from non-responders remain poorly understood. In this study, spatial multiomics, including imaging mass cytometry (n = 50 in-house), spatial proteomics (n = 50 in-house), and spatial transcriptomics (n = 9 in-house), were employed to elucidate the spatial TME of metastatic CRC (mCRC) patients receiving immunotherapy. These methodologies were integrated with single-cell RNA sequencing (scRNA-seq), bulk RNA-seq, and bulk proteomics for comprehensive analysis and validation. A spatial immune atlas containing 314,774 cells was constructed. We found that C1QC+ resident tissue macrophages (RTMs) were more abundant in responders regardless of microsatellite status. Co-localization of C1QC+ RTMs with CD4+ T cells was observed in responders, and MHC-II expression facilitated their interaction. In contrast, cancer-associated fibroblasts inhibited this interaction in non-responders. Moreover, whole genome screening identified key genes involved in antigen presentation in C1QC+ RTMs. Hence, our study highlights the importance of spatial immune mapping in revealing the complex spatial topology of CRC and corresponding immunotherapy response. |
| format | Article |
| id | doaj-art-41ace406135e402ea3ee06a9f45db5bc |
| institution | Kabale University |
| issn | 2056-5968 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Discovery |
| spelling | doaj-art-41ace406135e402ea3ee06a9f45db5bc2025-08-20T03:37:28ZengNature Publishing GroupCell Discovery2056-59682025-07-0111112110.1038/s41421-025-00811-2Spatially resolved C1QC+ macrophage-CD4+ T cell niche in colorectal cancer microenvironment: implications for immunotherapy responseHangyu Zhang0Libing Hong1Zhen Dong2Shan Xin3Bo Lin4Jinlin Cheng5Weihong Tian6Bin Li7Jing Wang8Xiaoyan Liu9Chuan Liu10Yuzhi Jin11Yanzhi Feng12Ge Su13Xuqi Sun14Qiqi Liu15Xiaomeng Dai16Yang Gao17Zhou Tong18Lulu Liu19Xudong Zhu20Yi Zheng21Peng Zhao22Tiannan Guo23Weijia Fang24Xuanwen Bao25Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang UniversityDepartment of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang UniversityWestlake Center for Intelligent Proteomics, Westlake Laboratory of Life Sciences and BiomedicineDepartment of Genetics, Yale School of MedicineInnovation Centre for Information, Binjiang Institute of Zhejiang UniversityState Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang UniversityChangzhou Third People’s Hospital, Changzhou Medical Center, Nanjing Medical UniversityDepartment of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang UniversityInnovation Centre for Information, Binjiang Institute of Zhejiang UniversityDepartment of Pathology, The First Affiliated Hospital, School of Medicine, Zhejiang UniversityDepartment of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang UniversityDepartment of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang UniversityDepartment of lmmunobiology, Yale School of MedicineCollege of Computer Science, Zhejiang UniversityDepartment of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang UniversityDepartment of Radiation Oncology, First Affiliated Hospital, School of Medicine, Zhejiang UniversityDepartment of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang UniversityDepartment of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang UniversityDepartment of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang UniversityDepartment of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang UniversityDepartment of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang UniversityDepartment of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang UniversityDepartment of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang UniversityWestlake Center for Intelligent Proteomics, Westlake Laboratory of Life Sciences and BiomedicineDepartment of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang UniversityDepartment of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang UniversityAbstract Colorectal cancer (CRC), including both microsatellite instability (MSI) and microsatellite stability (MSS) subtypes, frequently exhibits intrinsic resistance to immunotherapy. However, the spatial tumor microenvironment (TME) and its role in distinguishing immunotherapy responders from non-responders remain poorly understood. In this study, spatial multiomics, including imaging mass cytometry (n = 50 in-house), spatial proteomics (n = 50 in-house), and spatial transcriptomics (n = 9 in-house), were employed to elucidate the spatial TME of metastatic CRC (mCRC) patients receiving immunotherapy. These methodologies were integrated with single-cell RNA sequencing (scRNA-seq), bulk RNA-seq, and bulk proteomics for comprehensive analysis and validation. A spatial immune atlas containing 314,774 cells was constructed. We found that C1QC+ resident tissue macrophages (RTMs) were more abundant in responders regardless of microsatellite status. Co-localization of C1QC+ RTMs with CD4+ T cells was observed in responders, and MHC-II expression facilitated their interaction. In contrast, cancer-associated fibroblasts inhibited this interaction in non-responders. Moreover, whole genome screening identified key genes involved in antigen presentation in C1QC+ RTMs. Hence, our study highlights the importance of spatial immune mapping in revealing the complex spatial topology of CRC and corresponding immunotherapy response.https://doi.org/10.1038/s41421-025-00811-2 |
| spellingShingle | Hangyu Zhang Libing Hong Zhen Dong Shan Xin Bo Lin Jinlin Cheng Weihong Tian Bin Li Jing Wang Xiaoyan Liu Chuan Liu Yuzhi Jin Yanzhi Feng Ge Su Xuqi Sun Qiqi Liu Xiaomeng Dai Yang Gao Zhou Tong Lulu Liu Xudong Zhu Yi Zheng Peng Zhao Tiannan Guo Weijia Fang Xuanwen Bao Spatially resolved C1QC+ macrophage-CD4+ T cell niche in colorectal cancer microenvironment: implications for immunotherapy response Cell Discovery |
| title | Spatially resolved C1QC+ macrophage-CD4+ T cell niche in colorectal cancer microenvironment: implications for immunotherapy response |
| title_full | Spatially resolved C1QC+ macrophage-CD4+ T cell niche in colorectal cancer microenvironment: implications for immunotherapy response |
| title_fullStr | Spatially resolved C1QC+ macrophage-CD4+ T cell niche in colorectal cancer microenvironment: implications for immunotherapy response |
| title_full_unstemmed | Spatially resolved C1QC+ macrophage-CD4+ T cell niche in colorectal cancer microenvironment: implications for immunotherapy response |
| title_short | Spatially resolved C1QC+ macrophage-CD4+ T cell niche in colorectal cancer microenvironment: implications for immunotherapy response |
| title_sort | spatially resolved c1qc macrophage cd4 t cell niche in colorectal cancer microenvironment implications for immunotherapy response |
| url | https://doi.org/10.1038/s41421-025-00811-2 |
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