NGF pathway drives tumour growth

Innate lymphoid cells type 2 (ILC2s) are key regulators of tissue homeostasis and inflammation. In cancer, ILC2s can exhibit pro-tumoral functions by increasing the myeloid-derived suppressor cells (MDSC)/T-cell ratio. Nevertheless, the upstream ILC2 triggers remain poorly defined. Here, the authors identify nerve growth factor (NGF) as the driver of ILC2 pro-tumoral functions in patients with bladder cancer. They show that ILC2s express the NGF receptor TrkA and respond to NGF by secreting type-2 cytokines. In the tumour microenvironment, NGF-producing mast cells accumulate and activate ILC2s to induce regulatory T cells (Tregs), ultimately fostering tumour growth. In patients, NGF levels inversely correlate with survival in ILC2-rich tumours, underscoring the clinical significance of this axis. In vivo administration of a selective TrkA inhibitor improves survival in orthotopic tumour-bearing female mice and sensitises them to immune checkpoint blockade (ICB). Overall, the authors identify NGF as an ILC2 activator that shapes pro-tumoral ILC2 functions. The blockade of TrkA⁺ ILC2s might represent a targetable strategy to improve survival, particularly in ICB-resistant patients.

Access the full article: https://doi.org/10.1038/s41467-026-69841-y

WHY IS THIS IMPORTANT?

Understanding how tumours modulate the immune system is crucial for improving cancer treatment. In this study, Camilla Jandus’ team investigated immune cell subsets involved in bladder cancer and identified a new pathway that promotes tumour growth. They found that, by producing nerve growth factor (NGF), mast cells can activate innate lymphoid cells type 2 (ILC2) via the TrkA receptor. Activated ILC2 release cytokines that increase regulatory T cells, which suppress the body’s ability to fight cancer. Higher levels of NGF were also associated with worse survival in patients. Importantly, blocking the NGF–TrkA pathway in mice reduced tumour growth, improved survival, and enhanced the effectiveness of immunotherapy. These findings reveal a new immune mechanism that tumours can exploit and suggest that targeting NGF signalling could improve bladder cancer treatment and patient outcomes.

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