Distal directives | Nature Immunology – Immunology Research

Solid tumors as well as tissue-draining lymph nodes are innervated by nociceptive neurons that can transmit sensory cues via the peripheral nervous system. In Cell, Zhang et al. identify an immunosuppressive axis in which distal tumors co-opt neuropeptide signaling via nociceptor neurons to alter tumor-draining lymph nodes (TDLNs) and suppress anti-tumor immune cell responses. Examining tumor tissues from individuals diagnosed with head and neck squamous cell carcinoma (HNSCC), they found that increased densities of TRPV1⁺ nociceptor neurons correlate with pain sensitivity and accumulation of tumor-associated macrophages (TAMs), but decreased lymphocyte infiltration. Spatial analysis of tumor tissues revealed close proximity between tumor cells and TAMs; further interrogation showed that these TAMs upregulate the endoplasmic reticulum (ER) stress-associated transcription factor ATF4, which, in turn, promotes tumor cell production of the neuronal activator SLIT2 and nociceptor innervation and activation. Using optogenetic activation in mouse tumor models, the authors identify a neural reflex arc via the trigeminal ganglia that links afferent tumor neurons to distal nociceptors that innervate TDLNs. SLIT2 induces expression of the neuropeptide CGRP by the afferent tumor-associated nociceptors as well as by efferent nociceptors in the TDLNs. This distal CGRP secretion alters the TDLN environment to suppress interactions between dendritic cells and T cells and hence the priming of anti-tumor cell responses. CGRP production in the TDLNs also promotes macrophage skewing to immunosuppressive M2-like cells, which reinforces the tumor-protective response locally and in the tumor. Interfering with the ATF4–SLIT2–CGRP axis or nociceptor denervation can reduce tumor growth by enhancing T cell activation in the TDLNs. Future work should explore the cellular targets of CGRP in the TDLNs and how this signaling alters cell–cell interactions and responses.

Original reference: Cell https://doi.org/10.1016/j.cell.2025.09.029 (2025)