Editorial: Immunoregulation by Adenosine Signaling in Infection and Inflammation

Xiangsheng Huang ^1* Weidong ZHAO ² Tingting Weng ³ Lei Shi ⁴ Xiaoyi Yuan ⁵

• ¹ Gastroenterology Research Center, Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, United States
• ² Henan Key Laboratory of Immunology and Targeted Drugs, School of Medical Technology, Xinxiang Medical University, Xinxiang, China
• ³ Department of Biochemistry and Molecular Biology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, United States
• ⁴ RNA Oncology Group, School of Public Health, Lanzhou University, Lanzhou, China
• ⁵ Department of Anesthesiology, Critical Care and Pain Medicine, University of Texas Health Science Center at Houston, Houston, United States

Adenosine receptors mediate diverse effects in inflammation, immunity, and tissue repair. The A2A receptor is predominantly anti-inflammatory, suppressing pro-inflammatory cytokines (e.g., TNF-α, IL-1β), reducing neutrophil activation, and promoting regulatory T cell (Treg) expansion, thus maintaining immune tolerance. A2B receptors exhibit context-dependent effects: in cancer, they foster immunosuppression by supporting a tumorpromoting microenvironment, while in inflammatory bowel disease (IBD), they mitigate inflammation and enhance tissue repair by promoting IL-10 production and macrophage polarization. Additionally, A1/A2A receptor crosstalk mitigates neuroinflammation in Alzheimer's disease, and inhaled adenosine analogs targeting these receptors show promise in reducing IL-17-driven inflammation. Collectively, adenosine balances pro-and antiinflammatory effects across various diseases, highlighting its potential as a therapeutic target for autoimmune disorders, chronic inflammation, and cancer. expression and glutamatergic signaling. Adenosine is known for its critical complementary role by modulating mitochondrial function, and neurovascular repair through its A2A and A3 receptors, which suppresses IL-6 production and inflammatory damage and enhances mitochondrial biogenesis (Csoka et al., 2007, Doyle et al., 2025). Additionally, adenosine's ability to regulate neurovascular coupling aligns with the observed improvements from digilanid C-ES therapy. This integrated approach underscores the therapeutic potential of combining adenosine modulation with digilanid C-ES to target metabolic dysregulation, inflammation, and neurovascular dynamics in CHF.MicroRNAs (miRNAs) and purinergic signaling exhibit a dynamic interplay in regulating inflammation and immune responses, offering promising therapeutic strategies. Zhou et al. highlights the critical role of microRNAs (miRNAs) as regulators of immune and inflammatory responses in diabetic nephropathy. miRNAs, such as miR-146a and miR-16 regulate adenosine receptor expression and downstream pathways, influencing macrophage polarization, cytokine suppression (e.g., IL-6, IL-1β), and T cell activity (Mastroianni et al., 2019, Tian et al., 2016).Conversely, adenosine signaling modulates miRNA expression, as demonstrated by methotrexate-induced adenosine release activating miR-181b to mitigate vascular inflammation (Sun et al., 2012). These bidirectional interactions highlight opportunities for combined miRNA-adenosine therapies to fine-tune immune balance in inflammatory diseases. In cancer therapy, anti-CD73 agents like Oleclumab enhance radio-immunotherapy efficacy by sustaining ATP-driven immune activation, as seen in the COAST trial, with Oleclumab and durvalumab. However, CD73 blockade risks exacerbating radiation pneumonitis due to unresolved ATP-driven NLRP3 inflammasome activation and IL-1β/IL-18 release, as observed in trials like PACIFIC. Balancing these effects requires precise modulation of ATP-adenosine dynamics to optimize anti-tumor immunity, underscoring the need for integrated strategies that harmonize miRNA regulation, adenosine signaling, and immune checkpoint modulation in therapeutic design.The findings emphasize the importance of individualized therapeutic strategies for targeting adenosine signaling, particularly in cancer and inflammatory diseases. Precision medicine approaches can optimize the timing, dosage, and delivery of CD73-targeted therapies to enhance anti-tumor efficacy while minimizing adverse effects,