Therapeutic Potential of A3 Adenosine Receptor Agonists in Pancreatic Ductal Adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, characterized by late diagnosis, profound chemoresistance, and a five‑year survival rate below 10%. Conventional therapies including surgery, radiation, and cytotoxic chemotherapy offer limited benefit due to the tumor’s genetic heterogeneity and dense desmoplastic stroma. Recent advances highlight adenosine receptor signaling as a pivotal regulator of PDAC biology, with the A₃ adenosine receptor (A₃AR) emerging as a promising therapeutic target. A₃AR is markedly overexpressed in malignant tissues while remaining low in adjacent normal cells, enabling selective modulation of tumor growth and survival pathways. Preclinical and early clinical studies of selective A ₃AR agonists, particularly Namodenoson, demonstrate inhibition of NF‑κB, Wnt/β‑catenin, and RAS signaling, leading to apoptosis, reduced proliferation, and enhanced chemosensitivity. Combination strategies integrating A₃AR agonists with chemotherapy, immunotherapy, targeted inhibitors, and stromal‑modifying agents show synergistic potential, addressing both intrinsic tumor signaling and extrinsic micro environmental barriers. Despite encouraging safety and efficacy profiles, challenges remain, including pathway redundancy, stromal resistance, and limited clinical validation. Future perspectives emphasize biomarker‑driven patient selection, mechanistic exploration of resistance, and translation into large‑scale randomized trials. Collectively, A₃AR agonists represent a novel class of precision therapeutics with the potential to reshape PDAC management and improve outcomes in a disease with few effective alternatives.