Tandem Chemoimmunotherapy by a Cascade-Responsive Molecular Prodrug br

The limited therapeutic effects of immunotherapy for most types ofcancer stimulates the pursuit for efficient methods to improve its response rate.Herein we report the design and synthesis of a cascade-responsive molecularprodrug for tandem chemoimmunotherapy. This molecular prodrugfirst releasesdoxorubicin (DOX) in the mildly acidic tumor microenvironment (TME) toinduce immunogenic cell death (ICD) of tumor cells. Caspase 3/7 released duringtumor cell apoptosis liberates NLG919 from the prodrug, which inhibits theactivity of indoleamine 2,3-dioxygenase (IDO) and results in relief of TMEimmunosuppression. Meanwhile, tumor-associated antigens and immune stim-ulatory cytokines released during ICD activate the immune response against thetumor, leading to synergistic chemoimmunotherapy. The efficacy of this prodrug isvalidated byin vitroandin vivoexperiments, demonstrating the success of thisstrategy for cancer treatment