Multifunctional\nNanoparticles Boost Cancer Immunotherapy\nBased on Modulating the Immunosuppressive Tumor Microenvironment

Abstract

Cancer immunotherapy has been a favorable\nstrategy for facilitating\nantitumor immunity. However, immune tolerance and an ultimate immunosuppressive\ntumor microenvironment (ITM) are primary obstacles. To achieve the\ngoals of remodeling the ITM and promoting cancer immunotherapy, a\nversatile nanoparticle codelivering shikonin (SK) and PD-L1 knockdown\nsiRNA (SK/siR-NPs) was reported. SK/siR-NPs are demonstrated to tellingly\ninduce the immunogenic cell death (ICD) of tumor cells, leading to\nincreased dendritic cell maturation. Moreover, SK/siR-NPs can cause\nan efficacious inhibition of PD-L1, leading to enhanced cytotoxic\nT lymphocyte response to tumor cells. Most importantly, SK/siR-NPs\ncan restrain lactate production via the downregulation of pyruvate\nkinase-M2 (PKM2) and eventually repolarize tumor associated macrophages\n(TAMs) from the M2-subtype to M1-subtype states. Meanwhile, SK/siR-NPs\nsuppress regulatory T lymphocytes to fight with the ITM. Overall,\nthe developed co-delivery system presents a significant potential\nfor cancer immunotherapy through simultaneously inducing ICD, repolarizing\nM2-TAMs, and relieving PD-L1 pathway-regulated immune tolerance.