Research progress of CD73-adenosine signaling regulating hepatocellular carcinoma through tumor microenvironment

Abstract

Adenosine signaling pathway is a kind of signal regulation hub widely existing in human body, which is involved in a series of physiological processes such as energy supply of body cells. CD73 is a highly concerned signaling protein in purine adenosine pathway, and its role in tumor development and prognosis has been paid more and more attention in recent years, especially in hepatocellular carcinoma (HCC). In this paper, the specific mechanism by which CD73-adenosine signaling regulates tumor microenvironment (TME) of liver cancer tumors was analyzed in detail, highlighting the importance of this pathway as a therapeutic target to combat tumor immunosuppression and enhance the anti-tumor immune response to prevent and treat hepatocellular carcinoma (HCC). In addition, a variety of current targeted therapeutic strategies for adenosine metabolic pathways are summarized, including the development of new drugs in the stage of preclinical research and clinical trials, and the mechanism of action, implementation possibility, and clinical effects of these therapies are discussed. By summarizing the latest scientific research results, in this review, we attempt to paint a panorama of the mechanism of adenosine action in tumor immunotherapy, with the aim to provide a solid theoretical basis and practical guidance for subsequent research and clinical application, ultimately promoting the development of more accurate and efficient tumor immunotherapy.

Keywords: Adenosine; Adenosine receptor; CD73-adenosine signaling pathway; Hepatocellular carcinoma; Tumor microenvironment.

Fig. 1

CD73 and adenosine receptors are highly expressed in the liver tissues of patients with hepatocellular carcinoma (HCC). CD73 and adenosine receptors are expressed in a variety of cells. The regulation of CD73-adenosine signals in the tumor microenvironment (TME) to inhibit HCC progression is a current research hotspot

Fig. 2

In the tumor microenvironment (TME) of hepatocellular carcinoma (HCC), the immune system is destroyed and rebuilt under an adverse environment, constituting hypoxia, low nutrition, low pH, and blood flow changes; this leads to the formation of a new systemic and local immune microenvironment that is suitable for tumor survival, regulating inflammation, and liver fibrosis, assisting tumors to escape immune system monitoring, leading to the occurrence and development of HCC

Fig. 3

The tumor microenvironment (TME) is an important internal environment in the occurrence and development of tumor diseases. In the TME, CD73 plays an important role in the occurrence, development, and metastasis of hepatocellular carcinoma (HCC) by promoting angiogenesis through immune escape, inflammatory cancer signaling transmission, adhesion molecular function, and neovascularization

Fig. 4

In the tumor microenvironment (TME), CD73 mediates the production and inhibition of inflammatory signaling molecules through the adenosine pathway. CD73 stimulates the production of inflammatory cytokines through various downstream signaling pathways, placing hepatocellular carcinoma (HCC) cells in a homeostasis environment with high expression of inflammatory cytokines, promoting the coexistence of inflammatory cells and cancer cells, and promoting the progression of HCC

Fig. 5

CD73 on tumor cells can effectively promote the formation of tumor blood vessels in the TME, and high expression of CD73 can also promote the proliferation and metastasis of cancer cells. CD73 can stimulate tumor neovascularization through multiple adenosine receptor pathways, as well as protect neovascularization and promote the growth and metastasis of hepatocellular carcinoma (HCC) in vivo

Fig. 6

CD73 is expressed in a variety of cells and binds to a variety of adenosine receptors (e.g., A1R, A2aR, A2bR, and A3R) on the surface of hepatocellular carcinoma (HCC) cells by catalyzing the production of adenosine in the tumor microenvironment (TME), thus activating downstream signaling pathways to play a protective role in the disease process and prognosis of HCC