Targeting the adenosinergic axis in cancer immunotherapy: Insights into A2A and A2B receptors and novel clinical combination strategies

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 A2A receptor (A2AAR) and the adenosine A2B receptor (A2BAR), which modulate diverse immune and stromal cell populations. A2AAR signaling suppresses the effector activity of cytotoxic T lymphocytes and natural killer cells, whereas A2BAR 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 A2AAR and A2BAR in immune, stromal, and tumor compartments. We critically analyze current strategies for developing selective and dual A2AAR/A2BAR 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 A2AAR and A2BAR 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 A2AAR/A2BAR 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 A2A (A2AAR) and A2B (A2BAR) receptors plays a central role in tumor-induced immunosuppression, limiting the efficacy of cancer immunotherapy. This review provides an integrated analysis of A2AAR and A2BAR functions across immune and stromal compartments, summarizes current selective antagonists (A2AAR and A2BAR) 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.