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The nerve to suppress tumor immunity

Pavel Hanč

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Vita > Cutting Edge > DOI: 10.15302/vita.2026.07.0050
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The nerve to suppress tumor immunity

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The presence of tertiary lymphoid structures is generally associated with a favorable prognosis in cancer, whereas tumor innervation correlates with adverse outcomes. Providing a mechanistic link between these clinical phenomena, in a recent study published in Cell, Ho et al. show that tumor-innervating nociceptors secrete the neuropeptide CGRP to inhibit the formation of tertiary lymphoid structures in lung adenocarcinoma, thereby promoting immune evasion.

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Nociceptors are traditionally understood as noxious stimuli sensors whose main purpose is to drive protective behaviors such as the withdrawal reflex or scratching. Nevertheless, the research over the last decade has demonstrated that these primarily afferent fibers also have efferent capabilities and can exert control over immunity in peripheral tissues. While nociceptors can, in some situations, promote inflammation, their role as protectors of tissue homeostasis and drivers of inflammation resolution has emerged as particularly prominent1,2.
Tumors are well known to exploit homeostatic, tissue-protective pathways that restrain immune activation, including regulatory T cells, anti-inflammatory cytokine networks, and myeloid-derived suppressor cells3. These mechanisms, while essential for preventing chronic inflammation and autoimmunity, create an immunosuppressive microenvironment that malignant cells can co-opt to evade immune surveillance. Consequently, it is of little surprise that tumors may also hijack nociceptor-driven neuroimmune axes and subvert these protective mechanisms to promote tumorigenesis. Accordingly, across multiple malignancies, nociceptors have been shown to inhibit leukocytes within the tumor microenvironment (TME)4, participate in inter-organ circuits that drive immunosuppression5, and directly support tumor cell survival6.
Now, a new study by Ho et al. has expanded the list of tumors that hijack nociceptors to include lung adenocarcinoma (LUAD)7. In an elegant series of experiments, the authors have shown that in a genetically engineered mouse model of LUAD, the tumor promotes local axonogenesis and sensitization of Nav1.8+ nociceptive fibers that also express calcitonin gene-related peptide (CGRP). Importantly, ablation of the lung nociceptive fibers as well as systemic CGRP antagonism suppressed tumor progression in an orthotopic LUAD model, while chemogenetic activation of Nav1.8+ fibers exacerbated the disease. Interestingly, the authors noted that nociceptor ablation correlated with an increased number of tertiary lymphoid structures (TLS) at the tumor periphery7.
TLS are ectopic lymphoid organs that form within non-lymphoid tissues in response to inflammation, with structure and organization that closely mirror those of secondary lymphoid organs, such as the lymph nodes. In tissues, including tumors, TLS act as “frontline” sites for antigen presentation and T-cell activation and, as a result, across malignant diseases, the presence of TLS correlates with better clinical outcomes. The formation of TLS is canonically driven by the lymphoid tissue inducer (LTi) cells, which secrete proinflammatory cytokines of the tumor necrosis factor (TNF) superfamily, TNFα and lymphotoxin α1β2 (LTα1β2), to activate the lymphoid tissue organizer (LTo) cells. Once initiated, LTo-derived chemokines, mainly CXCL13, CCL19, and CCL21, drive the organization and maturation of the TLS into a fully functional lymphoid organ8.
Consequently, the authors next set out to delineate how nociceptors inhibit TLS formation in LUAD. Using single-cell RNA sequencing, they identified a Tnfα-expressing Cd74+ tissue-resident interstitial macrophage population characterized by high levels of the CGRP receptor (Ramp1) expression as the candidate functional LTi cells that may be affected by nociceptors. Accordingly, using a combination of cell type-specific ablation, antibody blocking, and cell transfer experiments, the authors demonstrated that nociceptor-derived CGRP acted as a potent inhibitor of Ramp1High CD74+ macrophage activation, preventing Tnfa upregulation and stymying the TLS formation process. In contrast, in the absence of nociceptors, the TNFα-producing interstitial macrophages served as functional LTi cells, driving CXCL13 expression in LTo fibroblasts, thereby promoting TLS formation and potentiating anti-tumor immunity7 (Fig. 1).
Under steady-state conditions, nociceptors do not constitutively release neuropeptides without stimulation, raising the question of how CGRP release was triggered. Part of the answer may lie in the sensitized state of LUAD-innervating fibers that the authors noted early on, which suggests that tumor-derived factors may induce an injury-like state in nociceptors that supports neuropeptide release even in the absence of classical stimuli. Nonetheless, the authors focused their attention on another possibility. Smoking is a known risk factor for lung cancer, and cigarette smoke extract (CSE) accelerates disease progression in mouse models of LUAD. In addition, cigarette smoke behaves as an irritant that activates nociceptors through the TRPA1 channel. Accordingly, Ho et al. observed that intratracheal administration of CSE increased CGRP levels in the lung of mice, promoted tumor initiation in the autochthonous model of LUAD, and accelerated tumor progression in an orthotopic model7.
In human medicine, patients present with already established tumors. Consequently, it is important to understand whether targeting nociceptors could not only impede tumor development but also improve the efficacy of treatment. To that end, the authors used an orthotopic LUAD model where tumor-bearing mice were exposed to CSE in the presence or absence of the CGRP antagonist, olcegepant. Strikingly, when subjected to a regimen of immune checkpoint blockade (ICB) treatment with anti-PD-1 antibody, the olcegepant-pretreated animals showed delayed tumor growth and improved overall survival compared with the anti-PD-1-only group. Importantly, beyond merely strengthening the mechanistic link between cigarette smoke, CGRP, and lung cancer, these data demonstrate that CGRP pathway antagonists, an already-approved class of drugs, could prime tumors for checkpoint blockade — a therapeutically interesting option for patients undergoing ICB. In this regard, it is germane that anti-CGRP drugs are widely used to treat and prevent severe migraines9. Given the prominent role of CGRP in LUAD, it would be interesting to perform a retrospective epidemiological study to assess whether such treatment correlates with decreased tumor incidence.
Even though the present study has clearly delineated the roles and functions of immune cells, the exact identity of the neuronal fibers remains loosely defined. Lungs are innervated by Nav1.8+ nociceptors originating from vagal as well as dorsal root ganglia, with distinct functional and molecular identities, many of which can express CGRP10. Consequently, whether a specific subset of fibers is expanded in LUAD, and whether the tumor instructs a unique molecular identity in them, remain to be established. Similarly, the molecular mechanism(s) through which LUAD promotes neuronal growth and sensitization are not yet known. Finally, it is interesting to note that the early stages of tumorigenesis are rarely painful, yet nociceptors are clearly getting activated. How the transmission of sensory information and neuropeptide release in tumors is uncoupled represents a broader conceptual question that will be important for future studies to address.
While important biological questions remain, Ho et al. unambiguously demonstrated how LUAD engages nociceptors to subvert a pro-tissue repair neuroimmune axis to, ultimately, prevent TLS formation and stunt tumor immunity (Fig. 1). Conceptually, this represents a mechanism distinct from previously established roles of nociceptors in tumors, where they induced exhaustion of CD8+ T cells4, directly improved tumor cell survival6, or affected adaptive immunity development in tumor-draining lymph nodes5. Future research will need to establish to what extent these disparate mechanisms are unique to specific tumor types or whether they operate in parallel.

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The Author(s) 2026. Published by Higher Education Press. This is an Open Access article distributed under the terms of the CC BY license (https://creativecommons.org/licenses/by/4.0/).

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Hanč, P.  The nerve to suppress tumor immunity  Vita https://doi.org/10.15302/vita.2026.07.0050 ()
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