Cancer cachexia has long been viewed as a systemic inflammatory syndrome driven primarily by tumor-secreted molecules circulating through the bloodstream. Now, a study published in Science suggests that at least one subset of lung cancers may instead exploit the nervous system to trigger appetite loss and rapid weight loss, revealing a potential new avenue for therapeutic intervention.
Using mouse models and supporting clinical observations, researchers found that certain lung tumors produce prostaglandin E2 (PGE2), a lipid signaling molecule that activates sensory neurons in the lung. Those neurons transmit signals through the vagus nerve to appetite-regulating centers in the brainstem, ultimately driving anorexia and cachexia.
The findings challenge the prevailing view that circulating inflammatory cytokines are the primary drivers of cancer-associated wasting and instead point to direct neural communication between tumors and the brain.
“We found that there’s some subsets of lung cancer that are at high risk of developing cachexia,” said senior author Thales Papagiannakopoulos, PhD, from the Salk Institute. “We wanted to understand how the cachexia is actually mediated, and in particular the neurological symptoms related to anorexia—the lack of appetite.”
Cachexia affects up to 80% of patients with advanced cancer and contributes substantially to treatment intolerance, reduced quality of life, and mortality. Despite decades of research, effective therapies remain limited because the biological mechanisms underlying the syndrome have been incompletely understood.
One of the study’s most unexpected findings involved diet.
Clinicians have often recommended calorie-dense, high-fat foods to help patients maintain weight during cancer treatment. Instead, the investigators found that high-fat diets—particularly those rich in animal fats—accelerated cachexia in their lung cancer models.
“We found that high-energy, high-calorie, high-fat diets, particularly animal-containing fat, instead of delaying the weight loss and the cachexia, made it worse,” Papagiannakopoulos said. “That’s quite surprising, but important to know.”
The researchers traced this effect to prostaglandin E2, a bioactive lipid involved in inflammation and known to be regulated by drugs such as aspirin and ibuprofen. Tumors produced higher levels of PGE2 when animals consumed diets rich in animal fat, intensifying appetite loss.
Importantly, the investigators found little evidence that well-known cachexia-associated cytokines, including IL-6 and GDF15, were responsible for the anorexia observed in this model. Instead, the biology appeared to mirror mechanisms previously described during respiratory infections.
Studies of influenza and bacterial lung infections have shown that sensory neurons detect inflammatory signals in the lung and relay information directly to the brainstem, producing sickness behaviors such as reduced appetite, decreased activity, and diminished water intake.
Papagiannakopoulos and colleagues suspected lung tumors were co-opting this same pathway. “The tumors are sort of co-opting these infection-like scenarios,” he said. “They’re signaling to the neurons and, by doing so, directly connecting to the brain and not requiring factors in circulation.”
To test that hypothesis, the researchers disrupted communication between the lung and the brain in two different ways.
In one experiment, they surgically severed one branch of the vagus nerve, reducing neural signaling from the lung by approximately half. The intervention significantly improved anorexia. The team then used chemogenetics—a neuroscience technique that selectively turns specific neurons on or off—to inhibit only lung sensory neurons projecting to the brain. “When we did that, we could rescue the mice,” Papagiannakopoulos said. “They were able to eat and drink and move as if they didn’t have cachexia.”
While surgically interrupting the vagus nerve is unlikely to become a treatment for cancer cachexia, the experiments identified an actionable biological pathway that could be targeted pharmacologically.
One possibility is developing therapies that block the specific prostaglandin receptors on sensory neurons rather than broadly suppressing prostaglandin production with nonsteroidal anti-inflammatory drugs.
“We want to identify what receptors on the neurons prostaglandin E2 is signaling through,” Papagiannakopoulos said. “Then we could potentially use inhibitors against the specific receptors, which would be much more focused than using ibuprofen or aspirin.”
Another approach could involve neuromodulation. Devices that electrically stimulate the vagus nerve are already FDA-approved for certain inflammatory diseases, and early studies are exploring similar technologies in cancer patients.
The researchers ultimately hope to identify the precise population of vagal sensory neurons responsible for transmitting cachexia signals and determine where those neurons communicate within the brain.
Beyond cachexia, the work raises broader questions about how tumors communicate with the nervous system. Rather than acting solely through hormones and inflammatory proteins circulating in blood, cancers may directly manipulate neural circuits to produce many of the systemic symptoms experienced by patients.
“The brain acts as a central integrator of all these signals coming from the body,” Papagiannakopoulos said. “We actually think that a lot of the effects seen in cancer patients—some of them grouped under cachexia or other paraneoplastic syndromes—are mediated through the brain through these neural networks.”
If confirmed in patients, those neural pathways could represent an entirely new class of precision medicine targets aimed not at shrinking tumors themselves, but at preventing one of cancer’s most devastating complications.
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