Nanodrug Augmenting Antitumor Immunity for Enhanced TNBC Therapy via Pyroptosis and cGAS-STING Activation

Pyroptosis is a proinflammatory form of programmed celldeath thatresults in the release of cellular contents and activation of immuneresponses. However, GSDME (a pyroptosis-executed protein) is suppressedin many cancers. Herein, we constructed a nanoliposome (GM@LR) forcodelivering the GSDME-expressing plasmid and manganese carbonyl (MnCO)into TNBC cells. MnCO generated Mn2+ and carbon monoxide(CO) in the presence of H2O2. The CO-activatedcaspase-3, which cleaved the expressed GSDME, converting apoptosisto pyroptosis in 4T1 cells. In addition, Mn2+ promotedmaturation of dendritic cells (DCs) by the activation of STING signalingpathway. The increased proportion of intratumoral mature DCs broughtabout massive infiltration of cytotoxic lymphocytes, leading to arobust immune response. Besides, Mn2+ could be appliedfor magnetic resonance imaging (MRI)-guided metastasis detection.Taken together, our study showed that GM@LR nanodrug could effectivelyinhibit tumor growth via pyroptosis and STING activation combinedimmunotherapy.

Automated summary

In this study, a nanoliposome (GM@LR) was constructed for delivering the GSDME-expressing plasmid and manganese carbonyl (MnCO) into TNBC cells. MnCO generated Mn2+ and carbon monoxide (CO) in the presence of H2O2. CO-activated caspase-3 cleaved the expressed GSDME, converting apoptosis to pyroptosis in 4T1 cells. Additionally, Mn2+ promoted the maturation of dendritic cells (DCs) through the activation of the STING signaling pathway. The increased proportion of intratumoral mature DCs caused massive infiltration of cytotoxic lymphocytes, leading to a robust immune response.