Cancer cells co-opt an inter-organ neuroimmune circuit to escape immune surveillance

Yu Zhang; Yibo Guo; Zheqi Liu; Yiting Sun; Xi Yang; Mingtao Chen; Guanying Feng; Chengzhong Lin; Yang Wang; Zhen Zhang; Yun Zhu; Jinhai Ye; Jiajia Liu; Jun Shi; Xiaomeng Zhou; Qingjian Han; Yu Liu; Qian Jiang; Youcheng Yu; Xu Wang; Chenping Zhang; Yunfan Sun; Jian Zhou; Jia Fan; Tong Ji

doi:10.1016/j.cell.2025.09.029

Cancer cells co-opt an inter-organ neuroimmune circuit to escape immune surveillance

Cell. 2025 Oct 24:S0092-8674(25)01129-8. doi: 10.1016/j.cell.2025.09.029. Online ahead of print.

Authors

Yu Zhang¹, Yibo Guo², Zheqi Liu³, Yiting Sun⁴, Xi Yang⁵, Mingtao Chen³, Guanying Feng³, Chengzhong Lin³, Yang Wang³, Zhen Zhang³, Yun Zhu³, Jinhai Ye³, Jiajia Liu⁶, Jun Shi⁶, Xiaomeng Zhou⁷, Qingjian Han⁷, Yu Liu⁵, Qian Jiang⁸, Youcheng Yu⁸, Xu Wang⁵, Chenping Zhang⁹, Yunfan Sun¹⁰, Jian Zhou¹¹, Jia Fan¹², Tong Ji¹³

Affiliations

¹ Department of Oral and Maxillofacial Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China; Department of Stomatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
² Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China; Department of Stomatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
³ Department of Oral and Maxillofacial Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
⁴ Department of Oral and Cranio-Maxillofacial Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai 200011, China.
⁵ Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai 200011, China.
⁶ Department of Hematology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
⁷ State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai 200032, China.
⁸ Department of Stomatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
⁹ Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai 200011, China. Electronic address: zhang.chenping@hotmail.com.
¹⁰ Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China. Electronic address: yunfan_sun@msn.com.
¹¹ Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China. Electronic address: zhou.jian@zs-hospital.sh.cn.
¹² Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China. Electronic address: fan.jia@zs-hospital.sh.cn.
¹³ Department of Oral and Maxillofacial Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Shanghai Stomatological Hospital & School of Stomatology, Fudan University, Shanghai 201102, China. Electronic address: jitong_zsyy@fudan.edu.cn.

PMID: 41138728
DOI: 10.1016/j.cell.2025.09.029

Abstract

Whether and how cancer exploits distant organs to escape immune surveillance remains largely unknown. Using clinical data from head and neck squamous cell carcinoma (HNSCC) patients and three murine oral cancer models, we find that cancer cells under immune pressure secrete slit guidance ligand 2 (SLIT2) through an activating transcription factor 4 (ATF4)-dependent pathway, which activates tumor-innervating nociceptive neurons and aggravates cancer-induced pain. This activation then stimulates tumor-draining lymph-node (TDLN)-innervating nociceptive neurons and increases calcitonin gene-related peptide (CGRP) secretion, remodeling TDLNs into an immune-suppressed state. Consequently, decreased CCL5 secretion from immune-suppressed TDLNs promotes M2-like polarization of tumor-associated macrophages, facilitating tumor growth and reducing immune checkpoint blockade (ICB) efficacy. Targeting nociceptive neurons or the ATF4-SLIT2-CGRP axis restores immune activity, alleviates cancer-induced pain, and improves ICB responses. Our findings reveal an inter-organ neuroimmune circuit co-opted by cancer to escape immune surveillance, suggesting potential therapeutic strategies to enhance immunotherapy.

Keywords: CGRP; HNSCC; TAM; calcitonin gene-related peptide; cancer immunology; cancer neuroscience; head and neck squamous cell carcinoma; immune checkpoint blockade; lymph node; melanoma; nociceptive neuron; tumor microenvironment; tumor-associated macrophage.