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

Yu Zhang1, Yibo Guo2, Zheqi Liu3

  • 1Department 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.

Cell
|October 25, 2025
PubMed

Insights

Cancer cells escape immune surveillance by activating pain pathways, which suppress anti-tumor immunity. Targeting this neuroimmune circuit can restore immune function and improve immunotherapy efficacy.

Area of Science:

  • Oncology
  • Neuroimmunology
  • Cancer Immunology

Background:

  • Cancer immune evasion is a critical challenge in oncology.
  • The role of distant organ interactions in cancer immune escape is poorly understood.
  • Head and neck squamous cell carcinoma (HNSCC) provides a model to study these mechanisms.

Purpose of the Study:

  • To elucidate the mechanisms by which cancer exploits distant organs to evade immune surveillance.
  • To investigate the role of the nervous system in cancer-induced immune suppression.
  • To identify potential therapeutic targets for enhancing cancer immunotherapy.

Main Methods:

  • Analysis of clinical data from HNSCC patients.
  • Utilized three murine oral cancer models.
  • Investigated the ATF4-SLIT2-CGRP signaling axis and its impact on nociceptive neurons and lymph nodes.

Main Results:

  • Cancer cells under immune pressure secrete SLIT2 via ATF4, activating nociceptive neurons and causing pain.
  • This neuronal activation suppresses anti-tumor immunity in tumor-draining lymph nodes (TDLNs) by reducing CCL5 and promoting M2 macrophage polarization.
  • This immune suppression facilitates tumor growth and diminishes the effectiveness of immune checkpoint blockade (ICB).

Conclusions:

  • Cancer establishes an inter-organ neuroimmune circuit to escape immune surveillance.
  • Targeting nociceptive neurons or the ATF4-SLIT2-CGRP pathway can restore anti-tumor immunity.
  • This approach may enhance immunotherapy responses and alleviate cancer pain.
Keywords:
CGRPHNSCCTAMcalcitonin gene-related peptidecancer immunologycancer neurosciencehead and neck squamous cell carcinomaimmune checkpoint blockadelymph nodemelanomanociceptive neurontumor microenvironmenttumor-associated macrophage

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