Nanotherapeutic Platform-Mediated Cholesterol Metabolism Regulation for Boosting Antitumor Chemo-Immunotherapy
Chemotherapy induces immunogenic cell death (ICD) but is compromised by elevated cholesterol in the tumor microenvironment (TME), which activates myeloid-derived suppressor cells (MDSCs) and exhausts CD8+ T cells. A poly(lactide-co-glycolide) (PLGA)-based nanoplatform (COD/MTO@PLGA@FA) co-loading mitoxantrone (MTO) and cholesterol oxidase (COD) was engineered to respond to acidic TME, releasing MTO and COD. MTO kills tumor cells and triggers ICD; COD consumes cholesterol, downregulating PD-1 on tumor-infiltrating CD8+ T cells and inhibiting MDSC activation. In 4T1 tumor-bearing mice, COD/MTO@PLGA@FA plus αPD-L1 increased splenic CD4+ and CD8+ T cells from 63.4% to 72.3% and 25.7% to 32.5%, respectively. CD8+PD-1+ T cells decreased to 5.93% versus 35.9% (PBS), 31.4% (αPD-L1), 29.0% (MTO@PLGA), 23.0% (COD/MTO@PLGA), and 12.2% (COD/MTO@PLGA@FA). MDSC infiltration dropped from 16.3% to 2.25% (combination) and 6.14% (COD/MTO@PLGA@FA alone). DC maturation in tumor-draining lymph nodes reached 35.3% with the combination. The platform reverses CD8+ T cell exhaustion and remodels the immunosuppressive TME, significantly inhibiting tumor growth. This strategy offers a practical approach to enhance chemo-immunotherapy by targeting cholesterol metabolism.