Zhang Hangyu, Hong Libing, Dong Zhen, Xin Shan, Lin Bo, Cheng Jinlin, Tian Weihong, Li Bin, Wang Jing, Liu Xiaoyan, Liu Chuan, Jin Yuzhi, Feng Yanzhi, Su Ge, Sun Xuqi, Liu Qiqi, Dai Xiaomeng, Gao Yang, Tong Zhou, Liu Lulu, Zhu Xudong, Zheng Yi, Zhao Peng, Guo Tiannan, Fang Weijia, Bao Xuanwen
Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
Westlake Center for Intelligent Proteomics, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China.
Cell Discov. 2025 Jul 1;11(1):60. doi: 10.1038/s41421-025-00811-2.
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.
结直肠癌（CRC），包括微卫星不稳定（MSI）和微卫星稳定（MSS）亚型，常常对免疫疗法表现出内在抗性。然而，肿瘤空间微环境（TME）及其在区分免疫疗法应答者与无应答者方面的作用仍知之甚少。在本研究中，采用了空间多组学技术，包括成像质谱流式细胞术（内部样本n = 50）、空间蛋白质组学（内部样本n = 50）和空间转录组学（内部样本n = 9），以阐明接受免疫疗法的转移性结直肠癌（mCRC）患者的空间TME。这些方法与单细胞RNA测序（scRNA-seq）、批量RNA测序和批量蛋白质组学相结合，进行全面分析和验证。构建了一个包含314,774个细胞的空间免疫图谱。我们发现，无论微卫星状态如何，C1QC驻留组织巨噬细胞（RTM）在应答者中更为丰富。在应答者中观察到C1QC RTM与CD4 T细胞共定位，并且MHC-II表达促进了它们之间的相互作用。相反，癌症相关成纤维细胞在无应答者中抑制了这种相互作用。此外，全基因组筛选确定了C1QC RTM中参与抗原呈递的关键基因。因此，我们的研究突出了空间免疫图谱在揭示CRC复杂空间拓扑结构及相应免疫疗法反应方面的重要性。
