A new international study led by researchers at Moffitt Cancer Centre, the Karolinska Institutet and the University of Texas MD Anderson Cancer Centre 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 tumour-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 tumours, 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 tumours 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 Centre 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 tumour 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 signalling 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 tumours 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.

Source: H. Lee Moffitt Cancer Center & Research Institute