Yang Sheng, Gu Chao, Miao Xinsheng, Zuo Hao, Xu Wei, Zhang Yan, Tang Wei, Zhu Jianhua, Yuan Zheng, Gu Xinhua, Zhong Chenyi, Sun Yueming, Zhou Jiahui
Department of General Surgery, The Third Affiliated Hospital of Nanjing Medical University, Changzhou, China.
Department of General Surgery, The First Affiliated Hospital With Nanjing Medical University, Nanjing, Jiangsu, China.
J Immunother Cancer. 2025 Dec 31;13(12):e013763. doi: 10.1136/jitc-2025-013763.
is one of the most frequently mutated genes in colorectal cancer (CRC) and plays a crucial role in tumorigenesis, progression, immune evasion, and treatment resistance. The pronounced heterogeneity within -mutant CRC highlights the urgent need for more precise and personalized therapeutic approaches.
To investigate this heterogeneity, we employed single-cell RNA sequencing and spatial transcriptomics to comprehensively characterize the tumor microenvironment of -mutant CRC. Data preprocessing and clustering were performed using Scanpy. Spatial cell-type deconvolution was conducted via Cell2location, whereas intercellular communication and spatial dependencies were analyzed using CellChat, MISTy, and stLearn.
Our analyses revealed that -mutant tumor epithelial cells recruit Mono_ monocytes via the MDK_SDC4 signaling axis. Concurrently, surrounding Fib_ fibroblasts secrete collagen, which interacts with integrin receptors on -mutant epithelial cells and contributes to the exclusion of lymphocyte infiltration.
These cellular components collaboratively established an immunosuppressive spatial niche. These findings offer novel theoretical insights and potential targets for the development of immunoregulatory strategies tailored to -mutant CRC.
是结直肠癌（CRC）中最常发生突变的基因之一，在肿瘤发生、进展、免疫逃逸和治疗耐药性中起关键作用。-突变型CRC内明显的异质性凸显了对更精确和个性化治疗方法的迫切需求。
为了研究这种异质性，我们采用单细胞RNA测序和空间转录组学来全面表征-突变型CRC的肿瘤微环境。使用Scanpy进行数据预处理和聚类。通过Cell2location进行空间细胞类型反卷积，而使用CellChat、MISTy和stLearn分析细胞间通讯和空间依赖性。
我们的分析表明，-突变型肿瘤上皮细胞通过MDK_SDC4信号轴招募单核细胞。同时，周围的成纤维细胞分泌胶原蛋白，其与-突变型上皮细胞上的整合素受体相互作用，并有助于排除淋巴细胞浸润。
这些细胞成分共同建立了一个免疫抑制性空间生态位。这些发现为开发针对-突变型CRC的免疫调节策略提供了新的理论见解和潜在靶点。
