Rationally Engineered Adenosine A2A Decoy Receptor for Reversing Immunosuppression of Breast Cancer

Abstract The hypoxia‐adenosine axis drives tumor immune evasion by activating A2AR on immune cells, and current therapeutic strategies predominantly rely on small‐molecule antagonists. However, these agents face limitations including short plasma half‐life, off‐target effects on other adenosine receptors, and inability to remodel the physical barriers of solid tumors. To overcome these challenges, this work designs a novel adenosine‐A2AR protein inhibitor, A2AR^QTY‐Fc, which demonstrates a notably high binding affinity for NECA and exhibits good water solubility and stability both in vitro and in vivo. This protein effectively blocks T cell A2AR signaling and restores cytokine production disrupted by NECA. Furthermore, given that the immune rejection microenvironment of solid tumors can impede the physical contact‐dependent tumor immune killing, this work designs a hydrogel drug delivery system based on human hair keratin. In a mouse model of 4T1 breast cancer, in situ injection of A2AR^QTY‐Fc loaded keratin hydrogel significantly inhibited tumor growth, reduced extracellular matrix density, and promoted immune cell infiltration. These findings demonstrate that combining the A2AR^QTY‐Fc with keratin hydrogel‐mediated delivery not only disrupts the hypoxia‐adenosine immunosuppressive axis, but also physically remodels the tumor microenvironment, thereby establishing a dual‐targeted therapeutic paradigm for overcoming GPCR‐mediated immune evasion and matrix barriers in solid tumors.