The Neuroimmune Axis and Its Therapeutic Potential for Primary Liver Cancer

Abstract

The autonomic nervous system plays an integral role in motion and sensation as well as the physiologic function of visceral organs. The nervous system additionally plays a key role in primary liver diseases. Until recently, however, the impact of nerves on cancer development, progression, and metastasis has been unappreciated. This review highlights recent advances in understanding neuroanatomical networks within solid organs and their mechanistic influence on organ function, specifically in the liver and liver cancer. We discuss the interaction between the autonomic nervous system, including sympathetic and parasympathetic nerves, and the liver. We also examine how sympathetic innervation affects metabolic functions and diseases like nonalcoholic fatty liver disease (NAFLD). We also delve into the neurobiology of the liver, the interplay between cancer and nerves, and the neural regulation of the immune response. We emphasize the influence of the neuroimmune axis in cancer progression and the potential of targeted interventions like neurolysis to improve cancer treatment outcomes, especially for hepatocellular carcinoma (HCC).

Keywords: cancer immunity; cancer neuroscience; liver cancer.

Figure 1

Schematic of the autonomic innervation of the liver.

Figure 2

Multi-fluorescence image of an orthotopic hepatocellular carcinoma (HCC) in a syngeneic mouse liver. Nerve staining shows an abundance of intratumoral nerves. Green, TH; yellow, NF-H; red, PGP9.5; white, CD31; blue, DAPI.

Figure 3

Nerve–cell communication within tumors. Nerves infiltrate the tumor microenvironment and stimulate cancer cell growth and metastasis by releasing neurotransmitters like catecholamines, acetylcholine, and neuropeptides. This initiates signaling pathways for cancer cell growth and invasion via neurotrophin receptors (NTRs). Cancer cells release neurotrophic growth factors such as NGF, promoting nerve infiltration into the tumor, also known as axonogenesis or neo-neurogenesis, and also receptor tyrosine kinase (RTK)-mediated autocrine stimulation. This reciprocal interaction fuels tumor development and affects the tumor microenvironment, leading to inflammation and angiogenesis. Cancer-induced pain may also result from tumor innervation. PLCγ, phospholipase C γ; cAMP, cyclic adenosine monophosphate; PKC, protein kinase C. Adapted from Jonling et al. [37].