A novel prodrug and its nanoformulation suppress cancer stem cells by inducing immunogenic cell death and inhibiting indoleamine 2, 3-dioxygenase. (December 2021) - Guan, Jiankun
Abstract: Cancer stem cells (CSCs) present grand challenges for triple-negative breast cancer (TNBC). Conventional chemotherapy drugs, including Camptothecin (CPT), not only cannot eradicate CSCs but also foster a suppressive immune microenvironment for the initiation and proliferation of CSCs. Herein, we report a novel prodrug CPT–SS–NLG919 (CN) and its nanoformulation CN@PLA-HES-FA (CN@PHF), which potently suppress CSCs by regulating CSCs niche in murine TNBC 4T1 tumors. Via inducing immunogenic cell death (ICD) and simultaneous inhibiting indoleamine 2, 3-dioxygenase (IDO), CN and CN@PHF promote DC maturation, decrease Treg cells, mitigate tryptophan consumption, and reduce the amount of IL-6, IL-13, and TGF-β, converting CSCs niche to a hostile condition for CSCs to live in and eliminating CSCs efficiently, thereby inducing efficient tumor inhibition in 4T1 tumor models. Our work represents a new paradigm of eliminating CSCs by regulating tumor immune microenvironment and suggests that CN and its nanoformulation CN@PHF are promising candidates for the treatment of intractable TNBC. Highlights: Combining ICD induction and IDO inhibition can modulate CSCs niche, relieve CSCs dormancy and eliminate CSCs. A novel prodrug CN has good activity in inducing ICD and inhibiting IDO, thereby efficient inhibiting TNBC tumors. CN@PHF remodel CSCs niche by promoting DC maturation, reducing Treg cells, tryptophan consumption, IL-6, IL-13, and TGF-β.