An Injectable Hydrogel Reshaping Adenosinergic Axis for Cancer Therapy

Abstract Adenosinergic axis, an innate negative feedback mechanism known as converting adenosine triphosphate (ATP) to adenosine by ectonucleotidases CD39 and CD73, reverses the ATP‐mobilized immunogenic tumor microenvironment (TME) to an immunosuppressive TME caused by adenosine, incapacitating various immune cells (especially effector T cells) in tumor elimination. Herein, for the first time, an injectable hydrogel strategy to reshape the adenosinergic axis by metabolizing adenosine into the immunopotentiator compound inosine is reported for realizing a potent cancer therapy. The solution of adenosine deaminase (ADA), doxorubicin (DOX), benzene‐1,2,3‐tricarboxylic acid (BTC), and sodium alginate gelatinizes in situ in TME, results in an immunogenic niche reshaping the adenosinergic axis. The synergistic cooperation of DOX and BTC boosts ATP induction accompanied by a tumoricidal effect. Simultaneously, ADA catalyzed adenosine into inosine, not only regulating the accumulation of adenosine but also changing it into an immunopotentiator. This strategy possesses the advantage of narrowing the adenosine pool, enriching the ATP reservoir, and transforming the adenosinergic‐axis‐induced immunosuppressor adenosine into immunopotentiator inosine. Different from the A2A adenosine receptor blockade, this strategy achieves a cascade amplification of ATP‐based anti‐tumor immune response, enabling strong immunogenicity along with reversing the negative feedback of adenosinergic axis for powerfully suppressing tumor progression.