Scientists uncover molecular mechanism behind chemotherapy-induced peripheral neuropathy

Chemotherapy activates a stress sensor in immune cells, triggering inflammation and nerve damage, which may help explain why many cancer patients experience debilitating pain as a side effect, according to a new study by Weill Cornell Medicine and Wake Forest University School of Medicine researchers.

Up to half of all patients receiving chemotherapy experience chemotherapy-induced peripheral neuropathy (CIPN), which causes tingling, numbness and pain in the hands and feet. Since there are limited options to address this condition, patients are often forced to stop their cancer treatment early. The preclinical research, published Oct. 29 in Science Translational Medicine, may lead to strategies for preventing and controlling CIPN, as well as biomarkers for identifying patients at risk.

We uncovered a molecular mechanism that maps specifically to immune cells, not neurons. 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."

Dr. Juan Cubillos-Ruiz, senior author, the William J. Ledger, M.D. Distinguished Associate Professor of Infection and Immunology in Obstetrics and Gynecology, Weill Cornell Medicine

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

Piecing together a pain pathway

In previous findings, Dr. Cubillos-Ruiz and his colleagues showed that a pathway called IRE1α-XBP1, a molecular "alarm system" ignited in response to cellular stress in immune cells, also promotes pain after surgery and after inflammation in mouse models.

For this study, they used a well-established mouse model that closely reflects the nerve damage experienced by cancer patients. They discovered that a commonly-used chemotherapy called paclitaxel can trigger immune cells to produce high levels of reactive oxygen species—molecules that create cellular stress. This stress flips on the IRE1α switch, which pushes immune cells into a highly inflammatory state.

These hyperactive immune cells then travel to the dorsal root ganglia—the sensory nerve clusters that connect the limbs to the spinal cord—and release inflammatory molecules that irritate and damage nerves. This chain reaction produces the hallmark symptoms of CIPN: pain, cold sensitivity and nerve fiber loss.

Silencing IRE1α in immune cells using genetic techniques prevented this inflammatory surge and reduced CIPN-related behaviors in mice. The research team also used a drug that selectively inhibits IRE1α and is already in phase 1 clinical trials as a cancer treatment. Mice receiving chemotherapy together with the IRE1α inhibitor displayed reduced pain behaviors typically seen after paclitaxel treatment, and their nerves stayed 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.

Since IRE1α inhibitors are already being evaluated in patients with advanced solid tumors—where abnormal activation of this pathway is known to fuel cancer progression and therapy resistance—the new results raise the possibility that the same drugs could also protect patients from chemotherapy-induced nerve damage. According to Dr. Cubillos-Ruiz, such a dual benefit "could meaningfully improve both the effectiveness of cancer treatment and patients' quality of life."

A promising biomarker for patients

To see how their preclinical findings could translate to patients, the researchers conducted a small pilot study with women receiving paclitaxel for gynecologic cancers. They drew blood before and during each chemotherapy cycle and found that patients who later developed severe CIPN had higher activation of the IRE1α-XBP1 pathway in their circulating immune cells, even before symptoms appeared.

This means a blood test might eventually help identify individuals at highest risk of neuropathy, allowing for preventive measures—potentially including IRE1α inhibitors—before nerve damage occurs.