New Discovery May Prevent Debilitating Chemotherapy Nerve Pain

A hidden immune stress switch may be driving chemotherapy nerve pain, and scientists have found a way to turn it off.

A new study from researchers at Weill Cornell Medicine and Wake Forest University School of Medicine suggests that chemotherapy may trigger a stress response inside immune cells that leads to inflammation and nerve injury. This process could help explain why so many cancer patients develop severe pain while undergoing treatment.

Chemotherapy-induced peripheral neuropathy (CIPN) affects up to half of all people who receive chemotherapy. The condition commonly causes tingling, numbness, and pain in the hands and feet. Because there are few effective treatments, some patients are forced to cut back or stop their cancer therapy altogether. The preclinical findings, published in Science Translational Medicine, point to possible new ways to prevent or manage CIPN and may help identify patients who are most vulnerable.

“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 study was co-led by Dr. E. Alfonso Romero-Sandoval, professor of anesthesiology at Wake Forest University School of Medicine.

Tracing the Biological Chain Reaction Behind Pain

In earlier research, Dr. Cubillos-Ruiz and his team identified a stress-related pathway known as IRE1α-XBP1. This pathway acts as a molecular “alarm system” inside immune cells and becomes active when those cells are under strain. Previous experiments showed that this system can intensify pain after surgery and during inflammation in mouse models.

To explore its role in chemotherapy-related nerve damage, the researchers used a well-established mouse model that closely mirrors the symptoms seen in cancer patients. They found that paclitaxel, a widely used chemotherapy drug, causes immune cells to generate large amounts of reactive oxygen species — molecules that place cells under stress. This stress response activates IRE1α, pushing immune cells into a highly inflammatory mode.

Once activated, these immune cells migrate to the dorsal root ganglia — the sensory nerve clusters that connect the limbs to the spinal cord — where they release inflammatory signals that harm nearby nerves. This sequence of events leads to the classic signs of CIPN, including pain, heightened sensitivity to cold, and loss of nerve fibers.

Blocking a Key Stress Signal Protects Nerves

When the researchers genetically shut down IRE1α in immune cells, they prevented the surge of inflammation and significantly reduced CIPN-like symptoms in mice. The team also tested a drug that specifically blocks IRE1α and is already being studied in phase 1 clinical trials as a cancer therapy. Mice treated with both chemotherapy and the IRE1α inhibitor showed fewer pain-related behaviors after paclitaxel exposure, and their nerve tissue remained 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,” said Dr. Cubillos-Ruiz, who is also co-leader of the Cancer Biology Program at the Sandra and Edward Meyer Cancer Center at Weill Cornell.

Because IRE1α inhibitors are already being tested in patients with advanced solid tumors — where excessive activity of this pathway is known to drive cancer growth and resistance to therapy — the researchers say the same drugs might also help shield patients from nerve damage caused by chemotherapy. According to Dr. Cubillos-Ruiz, this combined benefit “could meaningfully improve both the effectiveness of cancer treatment and patients’ quality of life.”

Early Signs of a Predictive Blood Marker

To examine how their laboratory findings might translate to real patients, the researchers conducted a small pilot study involving women receiving paclitaxel for gynecologic cancers. Blood samples collected before and during chemotherapy cycles revealed that patients who later developed severe CIPN showed higher activity of the IRE1α-XBP1 pathway in their circulating immune cells, even before symptoms became noticeable.

These results suggest that a future blood test could help identify patients at highest risk for developing neuropathy, allowing doctors to take preventive steps — potentially including IRE1α inhibitors — before nerve damage begins.

Many Weill Cornell Medicine physicians and scientists maintain relationships and collaborate with external organizations to foster scientific innovation and provide expert guidance. The institution makes these disclosures public to ensure transparency. For this information, please see the profile for Dr. Juan Cubillos-Ruiz.

Reference: “Leukocyte-intrinsic ER stress responses contribute to chemotherapy-induced peripheral neuropathy” by Miriam M. Fonseca, Oriana Gelblung, Sarah D. Pennypacker, Taylor Brooks, Michael Limia, James W. Morgan, Xuewei Zhu, Luis C. Tovias-Sanchez, Alejandro Pluma-Pluma, Ruth Elena Martinez, Mathew R. Eber, Sun H. Park, Cristina M. Furdui, Deepika Awasthi, Alexander Emmanuelli, Byuri A. Cho, Chen Tan, David I. Shalowitz, Samuel S. Lentz, Michael Kelly, Anderson O’Brien Cox, Lindsay Macnamara, Fang-Chi Hsu, Yusuke Shiozawa, Wesley Hsu, Takao Iwawaki, Lance D. Miller, Glenn J. Lesser, Roy Strowd, Juan R. Cubillos-Ruiz and E. Alfonso Romero-Sandoval, 29 October 2025, Science Translational Medicine.
DOI: 10.1126/scitranslmed.ady5288

This 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.

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