Rutin: A Novel A2AR Antagonist with Promising Therapeutic Potential for Cancer Immunotherapy

Author(s): Sarah Kandoussi, Soumaya Rafii, Yassine El Ghallab, Souha Sahraoui, Abdallah Badoua.

Tumor cells evade immune surveillance through various mechanisms, including the upregulation of inhibitory immune checkpoints like the A2AR receptor. Targeting these checkpoints to reactivate anti-tumor immunity has become a major focus of cancer immunotherapy research. Recent efforts have explored the potential of natural molecules to modulate these checkpoints, aiming to minimize the side effects and high costs associated with antibody-based immunotherapies. In this study, we investigated rutin and eugenol, two naturally occurring compounds with reported therapeutic benefits, as potential A2AR antagonists. Our in silico docking analysis reveals that rutin binds to A2AR with high affinity and strong binding force, engaging three key amino acid residues implicated in tumor progression. This suggests that rutin may function as a potent A2AR antagonist, potentially reversing immune suppression and hindering tumor development. Furthermore, in vitro experiments using human peripheral blood mononuclear cells (PBMCs) demonstrated that rutin is non-toxic up to 900μM and, notably, exhibits a dose-dependent effect on succinate dehydrogenase (SDH) activity, a marker of mitochondrial function and metabolic activity. These findings suggest that rutin not only binds strongly to A2AR but also influences PBMC activity, warranting further investigation of its therapeutic potential in cancer immunotherapy.