2. Academic Validation
  3. Tumor-draining lymph nodes respond to immune checkpoint inhibition and orchestrate tumor immune remodeling

Tumor-draining lymph nodes respond to immune checkpoint inhibition and orchestrate tumor immune remodeling

  • Cancer Immunol Immunother. 2025 Oct 6;74(11):326. doi: 10.1007/s00262-025-04187-w.
Jinzhu Zhang 1,  Jian Ma 1,  Yaru Niu 1,  Jialiang Liu 1,  Zhexue Wang 1,  Jinyuan Guo 2,  Yongsheng Meng 3,  Ruifang Sun 3,  Zhen Zhang 4,  Haiyi Liu 5,  Juan Xu 6,  Likun Zan 7,  Xu Guan 8,  Xishan Wang 9
Affiliations

Affiliations

  • 1 Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 17 Panjiayuan South Lane, Chaoyang, Beijing, 100021, China.
  • 2 Shanxi Medical University, Taiyuan, 030001, China.
  • 3 Department of Tumor Biobank, Shanxi Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, 030013, China.
  • 4 Department of Pathology, Shanxi Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, 030013, China.
  • 5 Department of Colorectal Surgery, Shanxi Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, 030013, China.
  • 6 College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150086, China.
  • 7 Department of Pathology, Shanxi Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, 030013, China. zanlikun@hotmail.com.
  • 8 Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 17 Panjiayuan South Lane, Chaoyang, Beijing, 100021, China. drguanxu@163.com.
  • 9 Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 17 Panjiayuan South Lane, Chaoyang, Beijing, 100021, China. wxshan_1208@126.com.
PMID: 41051631 DOI: 10.1007/s00262-025-04187-w
Abstract

Background: Immune checkpoint inhibitors have traditionally been understood to exert their effects primarily within the tumor microenvironment, particularly targeting CD8 + T cells. However, recent studies have highlighted a pivotal role of tumor-draining lymph nodes in mediating responses to immune checkpoint inhibitor therapy. This study aimed to elucidate the specific mechanisms by which tumor-draining lymph nodes respond to immune checkpoint inhibitor therapy and regulate the tumor microenvironment in human colorectal Cancer.

Methods: We performed single-cell RNA Sequencing and T cell receptor Sequencing on tumor-draining lymph nodes and tumor tissues from patients with colorectal Cancer. Through in-depth analysis of the single-cell data, we established the connection between TDLNs and tumor, and explored the impact of immune checkpoint inhibitor therapy on the immune microenvironment of tumor-draining lymph nodes. In addition, we conducted animal experiments to validate these findings.

Results: Our findings revealed that immune checkpoint inhibitor treatment induced the expansion of tumor-specific CD8 + effector memory T cells within tumor-draining lymph nodes, which may serve as a source for the progenitor-exhausted CD8 + T cells in the tumor microenvironment. Moreover, conventional dendritic cells type 1 and macrophages within tumor-draining lymph nodes facilitated this process. We also observed that immune checkpoint inhibitor therapy promoted the expansion of tumor-specific CD4 + follicular helper T cells in tumor-draining lymph nodes, which may explain the increase of CD4 + follicular helper T cells in the tumor microenvironment after immune checkpoint inhibitor therapy. These hypotheses were corroborated through experiments in mice.

Conclusions: Our findings delineate the critical regulatory function of tumor-draining lymph nodes in modulating the tumor microenvironment during Immune checkpoint inhibitor therapy.

Keywords

Colorectal cancer; Immune checkpoint inhibition; Tumor-draining lymph nodes.

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