Lymph nodes molecular subtypes unravel lymph nodes heterogeneity and clinical implications in colorectal cancer

Xu Guan, Yueyang Zhang, Ruifang Sun, Guiyu Wang, Xiaoman Bi, Zhen Zhang, Likun Zan, Yongsheng Meng, Yunxiao Liu, Jinyuan Guo, Jian Ma, Jiale Li, Hanqing Hu, Yixun Zhang, Xin Zhang, Maoxi Liu, Bo Jiang, Haiyi Liu, Shuangmei Zou, Yanfeng Xi (), Haitao Zhou (), Wenqi Bai (), Deng Wu () and Xishan Wang ()
Additional contact information
Xu Guan: Chinese Academy of Medical Sciences and Peking Union Medical College
Yueyang Zhang: Chinese Academy of Medical Sciences and Peking Union Medical College
Ruifang Sun: Chinese Academy of Medical Sciences, Cancer Hospital Affiliated to Shanxi Medical University
Guiyu Wang: Nangang District
Xiaoman Bi: Hainan Medical University
Zhen Zhang: Chinese Academy of Medical Sciences, Cancer Hospital Affiliated to Shanxi Medical University
Likun Zan: Chinese Academy of Medical Sciences, Cancer Hospital Affiliated to Shanxi Medical University
Yongsheng Meng: Chinese Academy of Medical Sciences, Cancer Hospital Affiliated to Shanxi Medical University
Yunxiao Liu: Nangang District
Jinyuan Guo: Shanxi Medical University
Jian Ma: Chinese Academy of Medical Sciences and Peking Union Medical College
Jiale Li: Chinese Academy of Medical Sciences, Cancer Hospital Affiliated to Shanxi Medical University
Hanqing Hu: Nangang District
Yixun Zhang: Chinese Academy of Medical Sciences, Cancer Hospital Affiliated to Shanxi Medical University
Xin Zhang: Chinese Academy of Medical Sciences, Cancer Hospital Affiliated to Shanxi Medical University
Maoxi Liu: Chinese Academy of Medical Sciences, Cancer Hospital Affiliated to Shanxi Medical University
Bo Jiang: Chinese Academy of Medical Sciences, Cancer Hospital Affiliated to Shanxi Medical University
Haiyi Liu: Chinese Academy of Medical Sciences, Cancer Hospital Affiliated to Shanxi Medical University
Shuangmei Zou: Chinese Academy of Medical Sciences and Peking Union Medical College
Yanfeng Xi: Chinese Academy of Medical Sciences, Cancer Hospital Affiliated to Shanxi Medical University
Haitao Zhou: Chinese Academy of Medical Sciences and Peking Union Medical College
Wenqi Bai: Chinese Academy of Medical Sciences, Cancer Hospital Affiliated to Shanxi Medical University
Deng Wu: Hainan Medical University
Xishan Wang: Chinese Academy of Medical Sciences and Peking Union Medical College

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Lymph nodes (LNs) play a pivotal role in colorectal cancer (CRC) progression and immunity, yet their molecular and functional diversity remains poorly understood. By analyzing 630 LNs and 88 primary tumors from 200 CRC patients across four independent cohorts using bulk and single-cell RNA sequencing, we identify four non-metastatic negative LNs (NLN) subtypes (NLN_C1-C4) exhibiting obviously different immune function and stromal expansion. NLN_C3/C4 are characterized by diminished T and B cell activity and fibroblast-driven fibrosis, with follicular dendritic cell loss contributing to B cell dysfunction. Immune checkpoint inhibitors partially reverse these effects, restoring FDC and B cell activity. LNs subtypes demonstrate heterogeneity across patients and within individuals, with higher NLN_C3/C4 proportions associated with advanced tumor stages, poorer survival, and recurrence. Here, we report LNs subtypes as critical manifestations of LN heterogeneity in CRC, providing a basis for improved clinical stratification and LN-targeted therapeutic strategies.

Date: 2025
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DOI: 10.1038/s41467-025-63200-z

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