A new international study led by researchers at Moffitt Cancer Center , the Karolinska Institutet and the University of Texas MD Anderson Cancer Center has uncovered a surprising mechanism of resistance to immunotherapy: cancer's ability to injure nearby nerves.
The study, published in Nature , shows that when cancer cells infiltrate and damage tumor-associated nerves, it triggers an inflammatory response that ultimately weakens the effectiveness of anti-PD-1 immunotherapy. This widely used treatment works by unleashing the body's immune system to attack tumors, but many patients fail to respond.
"Our findings demonstrate that cancer-induced nerve injury is not just a bystander effect, it directly shapes the immune environment in ways that allow tumors to evade treatment," said Kenneth Tsai, M.D., Ph.D. , co-corresponding author of the study and co-director of Moffitt's Donald A. Adam Melanoma and Skin Cancer Center of Excellence . "Importantly, we also found that this process is reversible."
Using patient samples including those from recent neoadjuvant therapy trials and preclinical models of cutaneous squamous cell carcinoma, melanoma, gastric cancer and pancreatic cancer, the team showed that cancer cells degrade the protective myelin sheath of nearby nerves. The injured neurons release inflammatory signals, including IL-6 and type 1 interferons, which is able to be repaired initially, but over time creates a chronically suppressive tumor microenvironment.
The researchers tested several strategies to disrupt this cycle. Resistance to anti-PD-1 therapy was overcome by removing nerves that transmit pain, blocking key neuronal injury signals, or combining anti-PD-1 with drugs that target the IL-6 pathway.
"This work highlights a new role for the nervous system in cancer progression and resistance to therapy," Tsai said. "By targeting the signaling that follows nerve injury, we may be able to restore the immune system's ability to fight cancer."
The discovery could lead to new treatment combinations that improve outcomes for patients whose tumors invade and grow along nerves, a common feature in several cancer types associated with poor prognosis.
"This is an example of how studying the cross talk between cancer, nerves and the immune system can reveal entirely new actionable vulnerabilities," Tsai said.
The study was supported by the National Institutes of Health (CA016672, P30CA016672 and P30-CA076292).
About Moffitt Cancer Center
Moffitt is dedicated to one lifesaving mission: to contribute to the prevention and cure of cancer. The Tampa-based facility is one of only 57 National Cancer Institute-designated Comprehensive Cancer Centers , a distinction that recognizes Moffitt's scientific excellence, multidisciplinary research, and robust training and education. Moffitt's expert nursing staff is recognized by the American Nurses Credentialing Center with Magnet®
