The progress and prospects of targeting the adenosine pathway in cancer immunotherapy

Abstract

Despite the notable success of cancer immunotherapy, its effectiveness is often limited in a significant proportion of patients, highlighting the need to explore alternative tumor immune evasion mechanisms. Adenosine, a key metabolite accumulating in hypoxic tumor regions, has emerged as a promising target in oncology. Inhibiting the adenosinergic pathway not only inhibits tumor progression but also holds potential to enhance immunotherapy outcomes. Multiple therapeutic strategies targeting this pathway are being explored, ranging from preclinical studies to clinical trials. This review examines the complex interactions between adenosine, its receptors, and the tumor microenvironment, proposing strategies to target the adenosinergic axis to boost anti-tumor immunity. It also evaluates early clinical data on pharmacological inhibitors of the adenosinergic pathway and discusses future directions for improving clinical responses.

Keywords: Adenosine; Adenosine receptors; CD39; CD73; Cancer immunotherapy; Tumor microenvironment.

Fig. 1

Adenosine production and signaling pathway. Following cell death or cellular stress, ATP is rapidly released into the extracellular space through mechanisms such as vesicle exocytosis, ABC transporters, pannexin-1, connexins, and P2X7R. Extracellular ATP can then activate P2X and P2Y receptors or be converted into adenosine via the ectonucleotidases CD39 and CD73. The enzymatic action of CD39 can be reversed by AK and NDPK. Adenosine can also be produced via the CD38-CD203a-CD73 pathway. In addition to ectonucleotidases, alternative membrane-bound phosphatases, including TNAP and PAP, can contribute to adenosine generation. Once generated, extracellular ADO can bind to P1 receptors (A1R, A2AR, A2BR, and A3R), be degraded to inosine by ADA, or be transported into the intracellular space through equilibrative or concentrative nucleoside transporters (ENTs and CNTs, respectively). ATP, adenosine triphosphate; ADP, adenosine diphosphate; AMP, adenosine monophosphate; ABC, ATP-binding cassette; AK, adenylate kinase; NDPK, nucleoside diphosphate kinase; TNAP, tissue-non-specific alkaline phosphatase; PAP, prostatic acid peptidase; ADO, adenosine; ADA, adenosine deaminase; PNP, purine nucleoside phosphorylase

Fig. 2

Mutation and methylation of CD73, CD39, A2AR, and A2BR in the adenosine signaling pathway. The Cancer Genome Atlas (TCGA) analysis of mutation (A) and methylation (B) data for NT5E, ENTPD1, ADORA2A and ADORA2B, which encode the proteins CD73, CD39, A2AR, and A2BR, respectively, in human cancers. Data were retrieved from the TCGA database (https://portal.gdc.cancer.gov/). LUAD: Lung adenocarcinoma; LUSC: Lung squamous cell carcinoma; PRAD: Prostate adenocarcinoma; HNSC: Head and neck squamous cell; KIRC: Kidney renal clear cell carcinoma; UCEC: Uterine corpus endometrial carcinoma; PCPG: Pheochromocytoma and paraganglioma; LIHC: Liver hepatocellular carcinoma; COAD: Colon adenocarcinoma; READ: Rectum adenocarcinoma; PAAD: Pancreatic adenocarcinoma; BLCA: Bladder urothelial carcinoma; CESC: Cervical squamous cell carcinoma; CHOL: Cholangiocarcinoma; ESCA: Esophageal carcinoma; KICH: Kidney renal clear cell carcinoma; KIRP: Kidney renal papillary cell carcinoma; STAD: Stomach adenocarcinoma; THYM: Thymoma; THCA: Thyroid carcinoma; BRCA: Breast invasive carcinoma; GBM: Glioblastoma multiforme

Fig. 3

Single cell-type specific landscape of CD73, CD39, A2AR, and A2BR in the adenosine signaling pathway. Single-cell expression profiles of NT5E, ENTPD1, ADORA2A, and ADORA2B, which encode the proteins CD73, CD39, A2AR, and A2BR, respectively, in human cancers and normal tissues, were retrieved from the Human Protein Atlas (HPA) database (https://www.proteinatlas.org/)

Fig. 4

Immunosuppressive effects of adenosine within the tumor microenvironment. The tumor microenvironment is composed of a diverse array of immune and non-immune cells, each exhibiting distinct expression profiles of functional adenosine receptors and adenosine-generating enzymes, mainly including A2AR, A2BR, CD39, and CD73. Adenosine facilitates tumor immune evasion by impairing protective immune components such as DCs, NK cells, T cells, and neutrophils, while simultaneously promoting the activity of immunosuppressive cells, including Tregs, M2 macrophages, and MDSCs. Targeting the various adenosinergic pathways may effectively reverse the adenosine-mediated immunosuppressive microenvironment. DCs: Dendritic cells; NK cell: Natural killer cell; Treg cells: Regulatory T cells; MDSC: Myeloid-derived suppressor cell; Mø: Macrophage; CAF: Cancer-associated fibroblast

Fig. 5

Potential for combining inhibition of the adenosinergic pathway and other cancer immunotherapies. Co-targeting key components of the adenosinergic pathway, such as A2AR, A2BR, CD39, and CD73, offers synergistic therapeutic potential by modulating both tumor and immune cells. Furthermore, adenosinergic pathway inhibitors may be effectively combined with other cancer immunotherapies, such as immune checkpoint blockade (ICB) and adoptive cellular therapy (ACT), to improve treatment outcomes across various cancers. This strategy is under active investigation and will be further evaluated in large-scale clinical trials. Additionally, targeting adenosine deaminase (e.g., PEG-ADA), which promotes inosine generation, remains a potential approach, though it has yet to be tested