Many people going through chemotherapy experience pain, tingling, or numbness in their hands and feet.
This condition is called chemotherapy-induced peripheral neuropathy (CIPN), and it affects nearly half of all cancer patients receiving chemotherapy. A new study may explain why this happens—and how we might prevent it.
Researchers from Weill Cornell Medicine and Wake Forest University found that chemotherapy activates a stress response in immune cells, not just nerve cells.
This reaction causes inflammation and nerve damage, leading to the painful symptoms of CIPN. The findings were published in the journal Science Translational Medicine.
Dr. Juan Cubillos-Ruiz, one of the lead researchers, explained that the pain is not simply from the nerves being harmed directly. Instead, it starts with a special “alarm system” inside immune cells called the IRE1α-XBP1 pathway. This system switches on when cells are under stress.
In this study, scientists used mice to model the effects of a common chemotherapy drug called paclitaxel. They discovered that paclitaxel made immune cells release large amounts of molecules known as reactive oxygen species, which stress the cells. This stress triggered the IRE1α pathway, turning the immune cells highly inflammatory.
These inflamed immune cells then traveled to the dorsal root ganglia—areas of the body that help send signals from the limbs to the spine. There, they released chemicals that irritated and damaged nearby nerves. This caused symptoms such as pain, cold sensitivity, and loss of nerve fibers.
When the scientists blocked the IRE1α pathway in the immune cells, they were able to reduce the inflammation and nerve damage in the mice.
The researchers also tested a drug that stops IRE1α, which is already being used in early human trials for cancer. Mice that were given both chemotherapy and the IRE1α-blocking drug showed fewer signs of pain and had healthier nerves.
Dr. Cubillos-Ruiz said this approach could help patients continue chemotherapy without the painful side effects. Since the IRE1α pathway also plays a role in cancer growth and resistance to treatment, targeting it could improve both cancer outcomes and patient comfort at the same time.
The team also tested their theory in humans. In a small group of women being treated with paclitaxel for gynecologic cancers, researchers looked at blood samples taken before and during treatment.
They found that women who later developed serious CIPN already showed signs of IRE1α pathway activity early on—even before they had symptoms.
This raises the possibility of developing a blood test to predict which patients are at higher risk for CIPN. If doctors can spot these early warning signs, they might be able to give preventive treatments—like IRE1α-blocking drugs—before the nerve damage begins.
In summary, this research shows that chemotherapy pain may be driven by immune cell stress, not just nerve damage. Blocking the stress pathway could reduce suffering and help patients stick with their cancer treatments more comfortably.
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The study is published in Science Translational Medicine.
