Spatially resolved C1QC+ macrophage-CD4+ T cell niche in colorectal cancer microenvironment: implications for immunotherapy response

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

doi:10.1038/s41421-025-00811-2

Spatially resolved C1QC⁺ macrophage-CD4⁺ T cell niche in colorectal cancer microenvironment: implications for immunotherapy response

Cell Discov. 2025 Jul 1;11(1):60. doi: 10.1038/s41421-025-00811-2.

Authors

Hangyu Zhang^#¹, Libing Hong^#¹, Zhen Dong^#^{2

3

4}, Shan Xin^#⁵, Bo Lin^{6

7}, Jinlin Cheng⁸, Weihong Tian⁹, Bin Li¹, Jing Wang⁶, Xiaoyan Liu¹⁰, Chuan Liu¹, Yuzhi Jin¹, Yanzhi Feng¹¹, Ge Su¹², Xuqi Sun¹, Qiqi Liu¹³, Xiaomeng Dai^{1

14}, Yang Gao¹, Zhou Tong¹, Lulu Liu¹, Xudong Zhu¹, Yi Zheng¹, Peng Zhao^{1

14}, Tiannan Guo^{15

16

17}, Weijia Fang^{18

19

20}, Xuanwen Bao^{21

22}

Affiliations

¹ Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
² Westlake Center for Intelligent Proteomics, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China.
³ School of Medicine, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China.
⁴ Research Center for Industries of the Future, Westlake University, Hangzhou, Zhejiang, China.
⁵ Department of Genetics, Yale School of Medicine, New Haven, USA.
⁶ Innovation Centre for Information, Binjiang Institute of Zhejiang University, Hangzhou, Zhejiang, China.
⁷ School of Software Technology, Zhejiang University, Ningbo, Zhejiang, China.
⁸ State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
⁹ Changzhou Third People's Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou, Jiangsu, China.
¹⁰ Department of Pathology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
¹¹ Department of lmmunobiology, Yale School of Medicine, New Haven, USA.
¹² College of Computer Science, Zhejiang University, Hangzhou, Zhejiang, China.
¹³ Department of Radiation Oncology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
¹⁴ National Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou, China.
¹⁵ Westlake Center for Intelligent Proteomics, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China. guotiannan@westlake.edu.cn.
¹⁶ School of Medicine, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China. guotiannan@westlake.edu.cn.
¹⁷ Research Center for Industries of the Future, Westlake University, Hangzhou, Zhejiang, China. guotiannan@westlake.edu.cn.
¹⁸ Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. weijiafang@zju.edu.cn.
¹⁹ National Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou, China. weijiafang@zju.edu.cn.
²⁰ Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, Hangzhou, China. weijiafang@zju.edu.cn.
²¹ Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. xuanwen.bao@zju.edu.cn.
²² National Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou, China. xuanwen.bao@zju.edu.cn.

^# Contributed equally.

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.

Abstract

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