Mobilizing STING Pathway via a Cationic Liposome to Enhance Doxorubicin‐Induced Antitumor Immunity

Abstract The efficacy of anthracycline, such as doxorubicin (DOX), is facilitated by cancer cell‐intrinsic type I interferon (IFN‐I) signaling through the induction of immune responses. However, weak and chronic IFN‐I responses from rounds of chemotherapy lead to resistance against DNA damage and acquired resistance to the therapy. An exogenous supply of IFN‐I can improve the chemotherapeutic responses. Herein, a library of cationic liposomes is developed for the optimization of 1, 2‐dioleoyl‐3‐trimethylammonium‐propane (DOTAP) proportions to enhance the lysosome escape and tumor distribution of the stimulator of interferon genes (STING) agonist 2′,3′‐cyclic guanosine monophosphate‐adenosine monophosphate (cGAMP) and DOX. The cationic liposomes with 8% DOTAP release cGAMP into the cytoplasm and increase the concentration of DOX in the tumor by 1.5 times compared with the free drug. Upon accumulation at the tumor site, the optimized liposomes induce immunogenic cell death (ICD) and stimulate the STING signaling, thereby improving the production of endogenous IFN‐I and promoting dendritic cell maturation to mobilize T cell immunity. The tumor growth inhibition rate is 86%, and the median survival time is 1.6‐fold prolonged. This study offers a strategy to enhance the DOX‐induced immune response by activating the STING pathway to supply IFN‐I.