pH-sensitive tumor-tropism hybrid membrane-coated nanoparticles for reprogramming the tumor microenvironment and boosting the antitumor immunity

Metabolic dysregulation contributes not only to cancer development but also to a tumor immune microenvironment (TIME), which poses great challenges to chemo- and immunotherapy. Targeting metabolic reprogramming has recently emerged as a promising strategy for cancer treatment, but the lethality against solid tumors appears to be fairly restricted, partially due to the poor solubility of small molecule drugs. Herein, we construct a versatile biomimetic nanoplatform (referred to as HM-BPT) employing pHsensitive tumor-tropism hybrid membrane-coated Manganese oxide (MnO 2 ) nanoparticles for the delivery of BPTES, a glutamine metabolism inhibitor. Basically, hybrid membranes consisting of mesenchymal stem cell membranes (MSCm) and pH-sensitive liposomes (pSL) enable the biomimetic nanoplatform to target TME and escape from endo/lysosomes after endocytosis. The results reveal that HM-BPT treatment leads to remarkable tumor inhibition, cytotoxic T lymphocyte (CTL) infiltration, as well as M1 phenotype repolarization and stimulator of IFN genes (STING) pathway activation in macrophages in a 4T1 xenograft model. Furthermore, glutathione (GSH) depletion and oxygen (O 2 ) supply synergistically ameliorate the immunosuppressive status of the TME, boosting potent antitumor immune responses. Overall, our study explores an integrated therapeutic platform for TME reprogramming and immune activation, offering tremendous promise for cancer combination therapy.

Automated summary

A versatile biomimetic nanoplatform, HM-BPT, was developed to target the tumor microenvironment (TME) and deliver a glutamine metabolism inhibitor, BPTES. HM-BPT treatment showed significant tumor inhibition, infiltration of cytotoxic T lymphocytes (CTL), and activation of the STING pathway in macrophages. Furthermore, the combination of glutathione depletion and oxygen supply improved the immunosuppressive status of the TME and enhanced antitumor immune responses.