Lung Tumors Tap Into the Vagus Nerve Through PGE2, Offering New Clues to Cancer Cachexia in Mice

Cancer cachexia is not simply a matter of “not eating enough.” Patients experience ongoing muscle loss and sometimes lose fat as well, leaving the body increasingly weak and potentially unable to tolerate treatment. A study published in *Science* now links the appetite loss caused by some lung cancers to an unexpected form of short-range communication: tumors release prostaglandin E2 (PGE2) in the lungs, using sensory nerves to send signals of illness to the brainstem.

The research team compared three mouse lung cancer models with different genetic alterations and tumors growing in their original location in the lungs. Only tumors lacking the tumor suppressor gene Lkb1 caused pronounced cachexia, even though the mice in this group did not have larger or more numerous tumors. This difference shifted the study’s focus from tumor burden itself to whether specific tumors can alter the host’s feeding and metabolic state.

A high-fat diet originally intended to increase caloric intake instead caused the Lkb1-deficient group to eat less, lose weight more rapidly, and die earlier. Analysis showed that PGE2 was primarily elevated in fluid from the lungs harboring the tumors, rather than in the blood; the high-fat diet further increased this signal. The results support a local mechanism: tumors may directly stimulate nearby pulmonary sensory nerves without first releasing large quantities of factors into the systemic circulation.

When the researchers genetically prevented the tumors from producing PGE2, or reduced its production through pharmacological methods and a fish oil diet rich in omega-3 fatty acids, the mice experienced less weight loss and improved survival, without accompanying tumor shrinkage. Cutting or genetically suppressing vagus nerve-related signaling likewise increased food intake; after pulmonary sensory nerves were eliminated, PGE2 could no longer cause cachexia to the same extent. These results connect the “tumor–pulmonary nerve–brainstem” axis into a causal pathway that can be targeted.

The study also tested lung fluid from patients with lung cancer and found higher PGE2 levels in those who also had cachexia, providing preliminary support for relevance in humans. However, the human data currently consist mainly of observational associations, while the mechanistic and treatment experiments remain primarily in mice; the study also has not demonstrated that different lung cancer subtypes, other cancer types, or patients with existing cachexia all depend on the same pathway.

The finding therefore cannot be directly interpreted to mean that aspirin, ibuprofen, or fish oil can already treat cancer cachexia. Nonsteroidal anti-inflammatory drugs carry risks including bleeding and kidney and gastrointestinal complications, while effective doses, treatment timing, and patient selection all require clarification through clinical trials. NYU Langone, where the research team is based, and the senior researchers have filed patent applications related to the findings; the critical next step is to determine whether local PGE2 or neural signaling can serve as a reliable marker for patient stratification and improve appetite, muscle preservation, and treatment tolerance without causing excessive adverse effects.