Journal
ACS NANO
Volume -, Issue -, Pages -Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsnano.2c00192
Keywords
dichloroacetate; glycolytic metabolism; pyroptosis; immunogenic cell death; soluble PD-L1; immunotherapy
Categories
Funding
- National Key R&D Program of China [2021YFA1201200]
- National Natural Science Foundation of China [51973188, 21774109, 81872181, 82002836]
- Natural Science Foundation of Zhejiang Province [LY20H160025, LY21H160034, LY21H060003]
- Zhejiang Undergraduate Talent Project [2021R401214, 2021R401216]
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This study explores the potential of targeting mitochondria to induce pyroptosis and enhance immunotherapy in osteosarcoma. The researchers synthesized a mitochondria-targeting polymer micelle and demonstrated its ability to induce immunogenic pyroptosis in osteosarcoma cells. Combination therapy with this micelle and an anti-PD-L1 antibody showed promising results in suppressing tumor proliferation and activating T cells.
Pyroptosis has been reported to improve the immunosuppressive tumor microenvironment and may be a strategy to enhance osteosarcoma treatment. The extent to which modulation of mitochondria could induce tumor pyroptosis to enhance immunotherapy has not been characterized. We synthesized a mitochondria-targeting polymer micelle (OPDEA-PDCA), in which poly[2-(N-oxide-N,N-diethylamino)ethyl methacrylate] (OPDEA) was used to target mitochondria and the conjugated dichloroacetate (DCA) was used to inhibit pyruvate dehydrogenase kinase 1 (PDHK1). This conjugate induced pyroptosis through initiation of mitochondrial oxidative stress. We found that OPDEA-PDCA targeted mitochondria and induced mitochondrial oxidative stress through the inhibition of PDHK1, resulting in immunogenic pyroptosis in osteosarcoma cell lines. Moreover, we showed that OPDEA-PDCA could induce secretion of soluble programmed cell death-ligand 1 (PD-L1) molecule. Therefore, combined therapy with OPDEA-PDCA and an anti-PD-L1 monoclonal antibody significantly suppressed proliferation of osteosarcoma with prolonged T cell activation. This study provided a strategy to initiate pyroptosis through targeted modulation of mitochondria, which may promote enhanced antitumor efficacy in combination with immunotherapy.
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