Researchers at the Francis Crick Institute have revealed that sensory nerve signals interfere with the immune system's response to lung cancer. This previously unrecognized neuroimmune connection could be targeted to improve responses to immunotherapy.
In the new study, published in Cell, scientists also found that exposure to cigarette smoke further exploits this neuroimmune interaction, accelerating tumor growth in mice.
The effectiveness of the immune response against cancer depends not just on immune cells being present, but how they are organised within the tumor microenvironment – the surrounding network of cells and signals that can either support or suppress immune activity.
Researchers have been investigating how different components of this environment shape immune responses, but the role of nerves has remained largely unexplored.
In this study, the research team focussed on the nervous system's early warning mechanism, specialised nerves that identify extreme thermal, physical, or chemical threats and trigger protective responses. By activating and deactivating these sensory nerves in mice, they demonstrated that their presence in the microenvironment was actively supporting tumor growth.
In turn, they also found that lung tumors increase the growth and activity of these nerves, triggering the release of a chemical messenger called calcitonin gene-related peptide (CGRP).
Using cell and mouse models, they showed how CGRP interacted with immune cells called macrophages in the tumor microenvironment. Through this interaction CGRP prevented the formation of clusters of immune cells called tertiary lymphoid structures, that are linked to better outcomes for people with lung cancer.
When the researchers disrupted local sensory nerve activity, or directly blocked CGRP signalling, the formation of these immune structures was increased. This was accompanied by stronger immune responses and reduced tumor growth.
Because drugs that target CGRP signalling, by inhibiting CGRP receptors, are already used clinically in other conditions, including for migraines, the researchers hope this could be a new approach for improving the effectiveness of cancer immunotherapy.
Finally, because smoking is the biggest risk factor for developing lung cancer, the team then decided to investigate whether cigarette smoke affects this neuroimmune pathway. They showed that cigarette smoke extract increases neuronal activity and accelerates tumor progression. This reveals a mechanism by which smoking can promote cancer progression beyond its role in causing DNA damage.
Leanne Li, Head of the Crick's Cancer-Neuroscience Laboratory, said: "We're starting to see the tumor microenvironment in all its complexity and what this means for disease progression. We've shown that nerves are not just present in cancers but actively shaping the tumor microenvironment and how cells talk to one another. This opens a new direction for cancer research, one that brings neuroscience and immunology together, and could reveal entirely new therapeutic opportunities."
Ya-Hsuan Ho, co-first author and postdoctoral fellow at the Crick, said: "It's fascinating to observe how sensitive the immune response is to changes in its local environment. We've shown that increased neuronal activity is enough to reorganise the immune landscape of the tumor and this changes how we think about immune evasion. It's not just about the presence or absence of immune cells, it's also how they respond to their surroundings."
Even with the amazing progress we've seen in people benefitting from immunotherapy, a large proportion of lung cancers don't respond. This unique insight into tumor biology could offer a completely new angle to improve those responses. And because drugs targeting elements of this pathway already exist, it's an especially promising route to explore further."
Giacomo Bregni, co-first author and doctoral clinical fellow, Francis Crick Institute
This study will inform the future work of team InteroCANCEption, a Cancer Grand Challenges team led by Leanne Li, which was awarded up to £20 million, in March 2026 to take on the nervous system and cancer challenge. Cancer Grand Challenges is a global research initiative, co-founded by Cancer Research UK and the National Cancer Institute in the US, that brings together world-class interdisciplinary teams to tackle some of cancer's toughest challenges.
Dr David Scott, Director of Cancer Grand Challenges, said "Understanding how the brain might detect tumors and even influence how they grow is an emerging frontier in cancer research. This is why Cancer Grand Challenges is enabling team InteroCANCEption, led by Leanne Li, to explore this bi-directional tumor-nervous system connection and potentially develop innovative approaches that target the nervous system, expanding what is possible in cancer treatment."
Team InteroCANCEption is funded by Cancer Research UK and the National Cancer Institute through Cancer Grand Challenges.
Researchers develop pH and redox-sensitive systems to reduce immunotherapy toxicity