Adenosine signaling in tumor immune escape: metabolic checkpoints, myeloid suppression, and combination immunotherapy

Adenosine is a central metabolic regulator of tumor immune escape, shaping the tumor microenvironment (TME) through suppression of effector lymphocytes and reprogramming of myeloid populations. Extracellular adenosine is generated primarily via the ectonucleotidases CD39 and CD73 and signals through A2A (A2AR) and A2B (A2BR) receptors on T cells, NK cells, tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and dendritic cells. This pathway promotes T-cell exhaustion, inhibits cytotoxicity, and enhances myeloid-driven immunosuppression, creating metabolic and spatial barriers that limit the efficacy of immune checkpoint blockade, STING agonists, radiotherapy, and emerging photothermal or nanomaterial-based therapies. Preclinical studies demonstrate that targeting the adenosine axis-via CD39/CD73 inhibition, receptor blockade, or combination strategies-can restore immune effector function, reprogram suppressive myeloid niches, and potentiate antitumor immunity. Spatial and circulating biomarkers, including tumor and exosomal CD73, adenosine gradients, and TAM/MDSC infiltration, may guide patient stratification and optimize combinatorial immunotherapy. Integrating adenosine-targeted approaches with PD-1/PD-L1 blockade, STING agonists, or adoptive cell therapies offers a rational strategy to overcome resistance and improve therapeutic outcomes. This review summarizes recent experimental evidence on the mechanisms of adenosine-mediated immune suppression, highlights translational opportunities, and discusses strategies for personalized and combination therapies aimed at dismantling metabolic immune checkpoints in cancer.