Lymph nodes molecular subtypes unravel lymph nodes heterogeneity and clinical implications in colorectal cancer
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.
Authors
- Ruifang Sun (ORCID: https://orcid.org/0000-0002-4791-3734)
- L K Zan (ORCID: https://orcid.org/0009-0003-6048-6102)
- Jinyuan Guo (ORCID: https://orcid.org/0000-0003-2684-2639)
- Deng Wu (ORCID: https://orcid.org/0000-0003-3144-2007)
- Wenqi Bai (ORCID: https://orcid.org/0009-0003-9421-2513)
- Guiyu Wang (ORCID: https://orcid.org/0000-0003-2501-5017)
- Maoxi Liu
- Xiaoman Bi (ORCID: https://orcid.org/0000-0003-4464-5014)
- Jinchen Li (ORCID: https://orcid.org/0009-0002-3893-8128)
- Xu Guan (ORCID: https://orcid.org/0000-0003-0997-498X)
- Yixun Zhang (ORCID: https://orcid.org/0000-0002-6048-1956)
- Jianhua Ma (ORCID: https://orcid.org/0000-0001-9383-2559)
- Hanqing Hu (ORCID: https://orcid.org/0000-0003-4920-1033)
- Shuangmei Zou (ORCID: https://orcid.org/0000-0001-8539-6291)
- Yueyang Zhang (ORCID: https://orcid.org/0000-0001-9219-7637)
- Xin Zhang (ORCID: https://orcid.org/0000-0003-2138-5600)
- Zhen Zhang (ORCID: https://orcid.org/0000-0001-7825-2679)
- Bo Jiang (ORCID: https://orcid.org/0009-0000-9929-9943)
- Haitao Zhou (ORCID: https://orcid.org/0009-0001-6000-851X)
- Yunxiao Liu (ORCID: https://orcid.org/0000-0001-9637-0476)
- Haiyi Liu (ORCID: https://orcid.org/0000-0003-4289-8480)
- Yongsheng Meng (ORCID: https://orcid.org/0000-0001-8063-7682)
- Xishan Wang (ORCID: https://orcid.org/0000-0002-0471-3134)
Institutions
- Harbin Medical University (CN)
- Shanxi Medical University (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- National Cancer Center (US)
- Shanxi Provincial Cancer Hospital (CN)
- Second Affiliated Hospital of Harbin Medical University (CN)
- Second Hospital of Shanxi Medical University (CN)
- Cancer Hospital of Chinese Academy of Medical Sciences (CN)
- Hainan Medical College Hospital (CN)
- Hainan Medical University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-08-22
- DOI
- https://doi.org/10.1038/s41467-025-63200-z
- Citations
- 2
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 2.09
Funders
- National Natural Science Foundation of China
- National Key Research and Development Program of China