The Inhibitory Effect of Adenosine on Tumor Adaptive Immunity and Intervention Strategies

Adenosine (Ado), mainly produced by the hydrolysis of ATP, exhibits significantly elevated levels in the tumor microenvironment (TME) compared to normal tissues. Upon binding to adenosine receptors (AdoRs), Ado initiates downstream signaling pathways that suppress tumor antigen presentation and immune cell activation, thereby inhibiting tumor adaptive immunity. Ado downregulates major histocompatibility complex II (MHC II) and co-stimulatory factors expression on DCs and macrophages, thereby inhibiting antigen presentation to T cells. Ado inhibits the binding of the T cell receptor (TCR) to its ligand and transmembrane signal transduction on T cells, thus suppressing anti-tumor cytokines secretion and inhibiting T cell activation. Ado also inhibits the secretion of chemokines and the KCa3.1 channel, thereby suppressing the trafficking and infiltration of effector T cells into the tumor site. Moreover, Ado inhibits the cytotoxicity of T cells against tumor cells by promoting the secretion of immune-suppressive cytokines, increasing the expression of immune checkpoint proteins, and enhancing the activity of immune-suppressive cells. Due to the inhibitory effects of Ado on tumor adaptive immunity, reducing Ado production in the TME can exert significant anti-tumor immune effects and enhance the efficacy of other immunotherapies. Various inhibitors blocking Ado generation or AdoRs are now under preclinical or clinical development. Therefore, this article will summarize and analyze the inhibitory effects and molecular mechanisms of Ado on tumor adaptive immunity, as well as provide an overview of the latest advancements in targeting Ado pathways in anti-tumor immune responses.