Cancer Cells Exploit Neuroimmune Crosstalk to Evade Immunity

Cancer progression modulates immune regulation at a systemic level, but the mechanisms involved remain incompletely defined. To investigate changes in the systemic immune response in head and neck squamous cell carcinoma (HNSCC), Zhang, Guo, Liu, Sun, Yang, and colleagues analyzed tumor tissues from a retrospective cohort of patients with HNSCC (n = 69) and focused on the potential role of a specialized class of pain-sensing sensory neurons known as nociceptive neurons. Analysis of multiple immunofluorescence data, integrated with measures of patient preoperative pain burden, revealed that, in patients with high pain, high nociceptive neuron density correlated with the accumulation of tumor-associated macrophages (TAM). CODEX spatial analysis confirmed that nociceptive neuron–high tumor regions were specifically enriched in TAMs but not other immune cell populations, suggesting potential neuroimmune crosstalk between these two populations. Transcriptional analysis was performed on syngeneic mouse tongue xenograft models treated with or without macrophage depletion, indicating that, under immune pressure from TAMs, cancer cells engaged a stress response that upregulated ATF4. ATF4 subsequently induced cancer cell expression of multiple genes associated with axonogenesis and sensory neuron development, including SLIT2. SLIT2 activated tumor-innervating nociceptive neurons, which then led to downstream secretion of calcitonin gene-regulated peptide (CGRP) by nociceptive neurons that innervate tumor-draining lymph nodes (TLDN). Beyond increasing cancer-induced pain within the tumor, this pathway of ATF4–SLIT2–CGRP signaling also promoted tumor growth as TLDNs shifted to an immune-suppressed state. Specifically, CGRP released within TDLNs reduced CCL5 secretion and impaired CD8+ T-cell and dendritic cell activation. Immune-suppressed TDLNs promoted M2-like polarization of TAMs, accelerating tumor growth and diminishing immune checkpoint blockade (ICB) responses. Disrupting this circuit via nociceptive neuron inhibition or genetic targeting of Atf4 or Slit2 restored TDLN immune activity, alleviated cancer-induced pain, and improved ICB efficacy. Notably, rimegepant, a CGRP receptor antagonist clinically approved for migraine treatment, enhanced the efficacy of PD-L1 blockade in preclinical models, suggesting a translational opportunity for combined pain control and immunotherapy. These findings highlight a neuroimmune mechanism of tumor immune escape and propose potentially actionable strategies to improve cancer immunotherapy.Zhang Y, Guo Y, Liu Z, Sun Y, Yang X, Chen M, et al. Cancer cells co-opt an inter-organ neuroimmune circuit to escape immune surveillance. Cell 2025;188:6754–73.Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at https://aacrjournals.org/cdnews.