Summary: Tumors have a surprising and sophisticated way of surviving: they recruit the brain to help them hide. A groundbreaking study reveals that tumors can trigger a neural signaling pathway that suppresses the immune system. By “talking” to the brain via the vagus nerve, tumors stimulate the release of stress hormones like glucocorticoids.
These hormones effectively shut down the activity of T cells that would otherwise attack the cancer. This discovery of a liver-brain-adrenal axis explains why some immunotherapy treatments fail and opens a brand-new frontier in “neuro-immunology” for cancer treatment.
Key Facts
- Neural Hijacking: Tumors send signals through the sensory vagus nerve to the brain’s “command center” (the nucleus tractus solitarius).
- Immune Suppression: The brain responds by activating the adrenal glands to release glucocorticoids, which are potent inhibitors of the immune system.
- The “Brake” on T Cells: This hormonal surge prevents T cells from infiltrating the tumor, allowing the cancer to grow unchecked.
- Systemic Impact: This pathway doesn’t just protect the tumor locally; it can dampen the immune response throughout the entire body.
- New Treatment Path: By blocking these specific neural or hormonal signals, researchers were able to restore the immune system’s ability to fight the tumor, potentially making existing immunotherapies much more effective.
Source: Yale
A new Nature study shows how cancerous tumors help themselves grow by communicating with the brain.
In many tumors, nerves from our peripheral nervous system establish themselves in the cancerous tissue. The new study found that tumors can hijack these nerves to send signals to the brain. This, in turn, triggers activity that blocks immune cells from infiltrating the cancer, which enables cancer growth.
“Tumors are really smart,” says Chuyue Yu, a PhD student at Yale School of Medicine (YSM) and one of the study’s first authors. “They employ as many resources in the body they can get in touch with to promote their own growth.”
Principal investigator Rui Chang, PhD, associate professor of neuroscience and of cellular and molecular physiology at YSM, previously thought that the innervation of tumors could be bad for the cancer. He hypothesized that the nerves would detect them as invaders and send warning signals to the brain to remove the threat.
But to his surprise, his new study, done in collaboration with a team led by Chengcheng Jin, PhD, assistant professor at the University of Pennsylvania Perelman School of Medicine, revealed that disrupting sensory neurons in tumors caused them to shrink.
The team then sought to understand why this happens. Using animal models of lung adenocarcinoma, they experimented with inhibiting and activating various subpopulations of neurons to see how this impacted cancer growth.
They also used single cell sequencing to identify the types of neurons innervating tumors in the lung, as well as imaging techniques to visualize how nerve and cancer cells interacted with one another. Meanwhile, collaborators at the University of Pennsylvania studied the surrounding immune cells and their signaling in the cancer microenvironment.
Tumor-brain crosstalk blocks immune activity
Through these techniques, the researchers discovered that tumors cause nerves to send signals to the brain, and that activates sympathetic nervous system activity—the part of the nervous system that drives “fight-or-flight” response. This, in turn, triggers the release of the hormone norepinephrine at the cancer site.
Norepinephrine activates specialized macrophages—immune cells that act as the body’s first line of defense—residing in the lung, which then block another type of immune cell called T cells from attacking the cancer. As a result, the cancer progresses unimpeded.
“The tumor promotes its own growth through this crosstalk to the brain that inhibits the immune environment,” says Chang, who is also a member of Yale’s Wu Tsai Institute.
The study is one example of how tumors can adapt to a specific environment in a way that promotes its growth, he adds. Cancers can behave differently in various organs. And while some become significantly innervated, others have a total lack of innervation.
His team is interested in exploring how different types of tumors communicate with the brain from different organs, which could help explain why some cancers act more aggressively.
The findings could also inform future therapies that target the parts of the nervous system underlying brain-tumor communication to halt cancer growth, the researchers say.
“Our study helps give a better understanding of how the brain, a massive computation organ, deals with the tumor,” Chang says. “There’s lots of potential to use this to fight tumor growth.”
Funding: The research reported in this news article was supported by the National Institutes of Health (awards R01CA276664 and R01AT012041) and Yale University. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Additional support was provided by the Damon Runyon Cancer Research Foundation, the Alexander and Margaret Stewart Trust, the Allen Discovery Center, and the Division of Intramural Research.
Key Questions Answered:
A: Not exactly. While stress can impact the immune system, this study shows that the tumor itself acts as the stressor. It tricks the brain into creating a “stress response” specifically to neutralize the immune cells that are trying to kill it.
A: They use the vagus nerve—the body’s internal “superhighway.” Tumors release certain molecules that the nerve picks up and carries to the brain, essentially sending a fake “SOS” signal that leads to immune suppression.
A: In laboratory models, blocking this pathway significantly slowed tumor growth and made immunotherapy more successful. The hope is that “neuromodulation” (targeting the nervous system) will become a standard part of cancer therapy in the future.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this brain cancer research news
Author: Isabella Backman
Source: Yale
Contact: Isabella Backman – Yale
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Tumour–brain crosstalk restrains cancer immunity via a sensory–sympathetic axis” by Haohan K. Wei, Chuyue D. Yu, Bo Hu, Xing Zeng, Hiroshi Ichise, Liang Li, Yu Wang, Ruiqi L. Wang, Ronald N. Germain, Rui B. Chang & Chengcheng Jin. Yale
DOI:10.1038/s41586-025-10028-8
Abstract
Tumour–brain crosstalk restrains cancer immunity via a sensory–sympathetic axis
Body–brain communication has emerged as a key regulator of tissue homeostasis. Solid tumours are innervated by different branches of the peripheral nervous system and increased tumour innervation is associated with poor cancer outcomes.
However, it remains unclear how the brain senses and responds to tumours in peripheral organs, and how tumour–brain communication influences cancer immunity.
Here we identify a tumour–brain axis that promotes oncogenesis by establishing an immune-suppressive tumour microenvironment.
Combining genetically engineered mouse models with neural tracing, tissue imaging and single-cell transcriptomics, we demonstrate that lung adenocarcinoma induces innervation and functional engagement of vagal sensory neurons, a major interoceptive system connecting visceral organs to the brain.
Mechanistically, Npy2r-expressing vagal sensory nerves transmit signals from lung tumours to brainstem nuclei, driving elevated sympathetic efferent activity in the tumour microenvironment.
This, in turn, suppresses anti-tumour immunity via β2 adrenergic signalling in alveolar macrophages. Disruption of this sensory-to-sympathetic pathway through genetic, pharmacological or chemogenetic approaches significantly inhibited lung tumour growth by enhancing immune responses against cancer.
Collectively, these results reveal a bidirectional tumour–brain communication involving vagal sensory input and sympathetic output that cooperatively regulate anti-cancer immunity; targeting this tumour–brain circuit may provide new treatments for visceral organ cancers.
