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

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.