Nerves Stimulates Crosstalk between Gastric Cancer and Group 3 Innate Lymphoid Cells to Enhance Immunosuppression

The immunosuppressive tumor microenvironment (TME) enables cancer cells to evade clinical immunotherapies. Neural networks are vital components of the TME, and interactions between cancer cells, neuronal cells, and immune cells mediate immunosuppression. Hence, understanding the mechanisms of intercellular crosstalk could inform immunomodulatory approaches to enhance immunotherapy efficacy. Here, we found that the vagus nerve regulated the crosstalk between gastric cancer (GC) cells and group 3 innate lymphoid cells (ILC3s), boosting immune resistance in GC by enhancing programmed death ligand 1 (PD-L1) expression. Specifically, the infiltrated vagus nerve released acetylcholine (ACh) that elevated the expression of lipase ABHD16A in GC cells, facilitating the production and secretion of the metabolite lysophosphatidylserine (LysoPS) into the TME. LysoPS facilitated the proliferation and activation of ILC3s in TME, resulting in production of the cytokine interleukin (IL)-22 via the GPR34/AKT/STAT3 axis. In turn, IL-22 triggered the unfolded protein response (UPR) in GC cells, which led to an increase in PD-L1 expression that enhanced immune resistance. Importantly, targeting ACh or the crosstalk between GC cells and ILC3s significantly enhanced the efficacy of anti-PD-L1 immunotherapy. Serum levels of LysoPS and IL-22 were elevated in GC patients, particularly those with perineural invasion. Collectively, these findings provide valuable insights into the crosstalk between GC cells, nerve cells, and ILC3s that regulates immunosuppression and response to ant-PD-L1 immunotherapy, emphasizing the potential clinical significance of this axis for detecting and treating GC.