靶向癌症免疫治疗中的腺苷能轴：对 A(2A) 和 A(2B) 受体及新型临床联合策略的见解

The extracellular accumulation of adenosine is a central mechanism of immune evasion within the tumor microenvironment. Elevated adenosine levels-driven by hypoxia, chronic inflammation, and upregulated ectonucleotidase activity, primarily through ectonucleoside triphophate diphosphoydrolase 1 and ecto-5'-nucleotidase-induce profound immunosuppression and promote tumor progression. In this setting, adenosine acts mainly through 2 G protein-coupled receptors, the adenosine A 2A receptor (A 2A AR) and the adenosine A 2B receptor (A 2B AR), which modulate diverse immune and stromal cell populations.

A 2A AR signaling suppresses the effector activity of cytotoxic T lymphocytes and natural killer cells, whereas A 2B AR activation exerts broader effects by amplifying myeloid-derived immunosuppression, driving stromal remodeling, and fostering angiogenesis and metastatic dissemination. This review provides a comprehensive overview of the distinct and converging roles of A 2A AR and A 2B AR in immune, stromal, and tumor compartments.

We critically analyze current strategies for developing selective and dual A 2A AR/A 2B AR antagonists, with a focus on structure-activity relationships, scaffold optimization, and pharmacokinetic profiling.

In addition, we examine ongoing clinical trials and emerging combination therapies involving A 2A AR and A 2B AR antagonists in conjunction with immune checkpoint inhibitors, adoptive cell therapies, enzymatic axis blockade, radiotherapy, and classical chemotherapy.

We also underscore the therapeutic potential of dual A 2A AR/A 2B AR antagonists as a multitarget approach to counteract overlapping immunosuppressive mechanisms.

Overall, targeting the adenosine axis-particularly through dual receptor blockade-represents a promising strategy for reprograming the tumor microenvironment, reinvigorating antitumor immunity, and improving the efficacy of cancer immunotherapy. SIGNIFICANCE STATEMENT: Adenosine signaling via adenosine A 2A (A 2A AR) and A 2B (A 2B AR) receptors plays a central role in tumor-induced immunosuppression, limiting the efficacy of cancer immunotherapy.

This review provides an integrated analysis of A 2A AR and A 2B AR functions across immune and stromal compartments, summarizes current selective antagonists (A 2A AR and A 2B AR) and dual antagonists, and highlights compounds in clinical studies.

Moreover, it discusses synergistic combination strategies that integrate adenosine blockade with complementary immunotherapeutic and conventional approaches to enhance antitumor responses.