How Lung Tumors Hijack Nerves to Dodge the Immune System

The nervous system plays a central role in coordinating and controlling most of the body’s processes by translating sensory information into functional responses. As a result, it is often thought of as the master command center of the body. 

It may come as no surprise, therefore, that the function of the nervous system is increasingly being linked to different disease states. For example, the growing field of neuroimmunology is uncovering novel interactions between immune cells and the nervous system and investigating their roles in inflammation and autoimmune diseases such as multiple sclerosis (Nutma et al. 2019).

Similarly, research efforts have explored the interplay between the nervous system and cancer biology. Multiple studies have now shown that nerve fiber density significantly increases in tumor samples compared to non-neoplastic controls, and, what’s more, this increase correlates with more aggressive cancers and poor patient prognosis (Zahalka and Frenette 2020).

However, the precise roles and mechanisms underlying this phenomenon have remained elusive.

In this blog, we discuss a recent paper by Wei et al. (2026), which uncovered a new mechanism by which tumor cells use the nervous system to bolster their position in the body.

Are Nerves Present in Lung Tumors?

The team focused specifically on lung cancer, using the Kras-p53 (KP) mouse model of lung adenocarcinoma—the most common type of non-small cell lung cancer (NSCLC)—driven by activation of the oncogenic Kras gene and loss of the tumor-suppressor Trp53 gene.

Using 3D imaging, the researchers observed the envelopment and penetration of tumors by vagal sensory nerve (VSN) fibers, with significantly higher nerve densities in tumor masses than in adjacent healthy lung regions.

Suspecting that cancer cells were secreting factors to promote nerve growth, in vitro experiments were set up in which VSNs were treated with tumor explant supernatant (TES) or lung explant supernatant (LES) from healthy mice. TES-treated cells had more neurite outgrowth than their LES-treated counterparts, indicating that cancer cells produce some neurotrophic factors to stimulate nerve growth.

Which Vagal Sensory Neurons Infiltrate Lung Tumors?

There are various subpopulations within the VSNs that can regulate different functions. In the lung, the majority of vagal sensory fibers are from the NPY2R- or P2RY1-expressing subpopulations.

Wei et al. aimed to investigate the specific subpopulation associated with lung cancer. By genetic labeling of either NPY2R or P2RY1, they found only NPY2R+ nerves were present in lung tumors. Delving deeper into the specific phenotype of the lung-innervating VSNs, it was noted that the NPYR2+ neurons largely coexpressed TRPV1.

Remarkably, when the researchers specifically depleted either NPY2R+ or TRPV1+ neurons, the tumor burden of the lung was significantly reduced, and disease progression was markedly inhibited. This was not the case when P2RY1+ VSNs were ablated, indicating a critical role for NPY2R/TRPV1 neurons in promoting lung cancer.

How Do VSNs Affect Anti-Tumor Immunity?

So, how exactly are these neurons aiding and abetting the tumors? To answer this, the scientists decided to investigate the role of the immune system.

Using high-dimensional spectral flow cytometry, which enables simultaneous analysis of multiple populations at the single-cell level, the abundance of immune cell types was assessed in NPY2R- and TRPV1-depleted mice compared to non-depleted controls.

In mice that lacked NPY2R- or TRPV1-expressing neurons, there was an increase in the tumor-reactive T cells (IFNy+ CD4 and IFNy+ TNF+ CD8 T cells) in the lung and tumor-draining lymph nodes, but no increase was observed in the splenic T cells, suggesting that VSNs inhibit the anti-tumor immunity of T cells in the local tumor microenvironment (TME).

In addition, tumor-associated alveolar macrophages in mice deficient in NPY2R/TRPV1 neurons exhibited an immunostimulatory phenotype, with decreased expression of ARG1, a T cell-suppressive factor, and increased expression of MHCII, a T cell-activating factor.

These results point towards a role for NPY2R/TRPV1 neurons in stimulating the polarization of alveolar macrophages in the TME to the immunosuppressive state, thereby hindering anti-tumor T cell immunity and enabling tumor growth.

How Do Lung Tumors Signal to the Brain?

The next step was to understand the neural pathways mediating these effects. The researchers specifically activated the TRPV1+ VSNs in mice and assessed the induction of FOS, a commonly used marker of neuronal activity.

They observed activation of the VSN-to-RVLM axis, a pathway involved in the regulation of sympathetic outflow in respiratory homeostasis, through which lung-innervating sensory nerves transmit signals via the vagal nodose ganglia (VNG) to the rostral ventrolateral medulla (RVLM) in the brainstem, linking the lung to the brain. These data indicate that lung cancer cells are hijacking this pre-existing pathway for their own detrimental purposes.

Interestingly, the authors found that disruption of this pathway via the ablation of VSNs decreased noradrenaline levels, a known anti-inflammatory mediator, in the lung.

Key Takeaways: The Tumor–Brain Axis in Lung Cancer

Taken together, these data imply a model in which the activation of neurons by tumor-derived factors sends signals to the brain to stimulate noradrenaline production, which in turn acts on alveolar macrophages to induce their immunosuppressive state, inhibiting T cell anti-tumor responses and, thus, allowing tumor cells to thrive without resistance.

Wei et al. showed that inhibiting this neural pathway significantly impaired tumor growth, indicating a potential target for therapeutic intervention to treat patients suffering from cancer.