Researchers from Weill Cornell Medicine and Wake Forest University School of Medicine have identified a stress-response pathway in immune cells that is activated by chemotherapy and leads to painful nerve damage. In mice, blocking this pathway with a drug already in early-stage cancer trials reduced signs of nerve injury, and a small patient study suggests a blood test might one day predict who is most at risk.
Chemotherapy often causes peripheral neuropathy, a side effect marked by tingling, numbness and pain in the hands and feet. Up to about half of patients receiving chemotherapy develop this condition, known as chemotherapy-induced peripheral neuropathy (CIPN), and because effective treatments are limited, some patients must reduce or stop therapy early.
A preclinical study published on October 29 in Science Translational Medicine by teams at Weill Cornell Medicine and Wake Forest University School of Medicine describes a mechanism that appears to drive CIPN. According to Weill Cornell Medicine and ScienceDaily, the researchers found that the commonly used chemotherapy drug paclitaxel prompts immune cells to generate large amounts of reactive oxygen species, placing the cells under stress and activating a pathway known as IRE1α–XBP1.
Earlier work by the same group showed that IRE1α–XBP1 acts as a molecular "alarm system" in immune cells, switching on in response to cellular stress. In the new study, the authors report that this alarm pushes immune cells into a highly inflammatory state. These overactivated immune cells then travel to the dorsal root ganglia—the sensory nerve hubs that connect the limbs to the spinal cord—where they release inflammatory molecules that irritate and damage nerves, leading to pain, cold sensitivity and loss of nerve fibers.
"We uncovered a molecular mechanism that maps specifically to immune cells, not neurons," said co-senior author Dr. Juan Cubillos-Ruiz, the William J. Ledger, M.D. Distinguished Associate Professor of Infection and Immunology in Obstetrics and Gynecology at Weill Cornell Medicine. "This provides strong evidence that chemotherapy-induced neuropathy is not just a nerve issue but an immune-mediated inflammatory process driven by cellular stress responses." The research was co-led by Dr. E. Alfonso Romero-Sandoval, professor of anesthesiology at Wake Forest University School of Medicine.
In a mouse model that closely mirrors nerve damage seen in patients, silencing the IRE1α gene specifically in immune cells prevented the surge of inflammation and reduced CIPN-like pain behaviors. The team also tested a drug that selectively inhibits IRE1α and is already in phase 1 clinical trials as a cancer treatment. When mice received paclitaxel together with this IRE1α inhibitor, they showed fewer signs of pain typically associated with the chemotherapy drug, and their nerves appeared healthier.
"Our findings suggest that targeting IRE1α pharmacologically could mitigate neuropathy induced by taxanes, helping patients continue with their chemotherapy without the negative side effects of nerve damage," Dr. Cubillos-Ruiz said, according to Weill Cornell Medicine. Because IRE1α inhibitors are being evaluated in people with advanced solid tumors—where excessive activity of this pathway can support cancer growth and therapy resistance—the authors note that such agents might eventually offer dual benefits: improving cancer treatment while shielding patients from chemotherapy-related nerve injury.
To explore how the animal findings might translate to the clinic, the team conducted a small pilot study involving women receiving paclitaxel for gynecologic cancers. Blood samples collected before and during each chemotherapy cycle showed that patients who later developed severe CIPN had higher activation of the IRE1α–XBP1 pathway in circulating immune cells even before symptoms emerged. According to Weill Cornell Medicine and ScienceDaily, this early signal suggests a blood test could eventually help identify patients at highest risk of neuropathy, paving the way for preventive strategies—potentially including IRE1α inhibitors—before nerve damage occurs.
The research was supported by the National Cancer Institute and the National Institute of Neurological Disorders and Stroke of the National Institutes of Health, as well as the U.S. Department of Defense.
