Gut-Brain Axis Regulates Liver Anti-Tumor Immunity
Hepatic immunosuppression contributes to high mortality in liver cancer. Nerve activity has been implicated in peripheral immune response and tumor growth. Whether cholinergic neuroimmune interactions shape hepatocellular carcinoma (HCC) remains uncertain. Hepatic vagotomy significantly reduced primary and metastatic liver tumors in mice. These vagotomized livers exhibited anti-tumor immunity, notably elevated inflammatory and cytotoxic CD8+ T cell subsets. Pharmaceutical or genetic disruption of ACh activity regulated CD8+ T cell function via AChR Chrm3, while tumor growth was rescued in Rag1KO mice or following CD8+ T cell depletion. Beyond tumor-specific outcomes, vagotomy improved cancer-associated fatigue and anxiety-like behavior. As microbiota transplantation from HCC donors was sufficient to impair behavior, we performed microbiome sequencing throughout cohousing and microbiota transplantation studies. Tumor, rather than vagotomy, robustly altered fecal bacterial composition, increasing Desulfovibrionales and Clostridial taxa. This tumor microbiota was sufficient to promote anti-tumor CD8+ T cell immune features only within vagotomized, but not vagal-intact, tumor-free mice. We identify gut-brain ACh signaling as a critical, dynamic, and targetable arc to modulate liver immunity and cancer outcomes. Overall design: Eight samples were prepared for scRNA-seq. Solid RIL175 tumors were excised from Sham Vagatomy (SV) and Hepatic Vagatomy (HV) livers (n = 3 / group) 21 d following tumor initiation.  RIL175 tumor-bearing mice (n = 3 SV, 3 HV mice) from non-tumorous liver and matched (pooled) tumors.