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Inspired Epigenetic Modulation Synergy with Adenosine Inhibition Elicits Pyroptosis and Potentiates Cancer Immunotherapy
Author(s) -
Xiong Honggang,
Ma Xianbin,
Wang Xiaolong,
Su Wen,
Wu Lei,
Zhang Tian,
Xu Zhigang,
Sun ZhiJun
Publication year - 2021
Publication title -
advanced functional materials
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.069
H-Index - 322
eISSN - 1616-3028
pISSN - 1616-301X
DOI - 10.1002/adfm.202100007
Subject(s) - cancer research , tumor microenvironment , immunotherapy , pyroptosis , epigenetics , dna methyltransferase , adenosine , downregulation and upregulation , microbiology and biotechnology , immune system , programmed cell death , biology , apoptosis , methyltransferase , biochemistry , immunology , dna , methylation , tumor cells , gene
Overcoming innate or adaptive resistance to immune checkpoint inhibitor therapy in solid tumors with limited T‐cell responses remains challenging. Increasing evidence has indicated that epigenetic alterations, especially overexpression of DNA methyltransferase and immunosuppressive adenosine, are major obstacles to T cell activation. Here, a tumor microenvironment (TME) inspired prodrug nanomicelle (AOZN) composed of the epigenetic modulator γ‐oryzanol (Orz), the adenosine inhibitor α, β‐methylene adenosine 5′ diphosphate (AMPCP), and GSH‐activable crosslinker, is rationally designed. High glutathione redox triggers Orz and AMPCP release in the TME. The released Orz act as a DNA methyltransferases inhibitor to upregulate gasdermin D (GSDMD) expression and AMPCP converted procaspase‐1 into active caspase‐1 by increasing ATP levels. Active caspase‐1 elicited GSDMD cleavage and induced pyroptosis in tumor cells. Furthermore, it is demonstrated that Orz and AMPCP likely have a synergistic effect in combating the immunosuppressive TME. Moreover, Orz enhances programmed death‐ligand 1 (PD‐L1) expression and sensitize tumors to anti‐PD‐L1 therapy. Thus, the AOZNs nano‐formulation drastically improves the hydrophobic properties of Orz with advantages of safe, affordable, readily available, and efficiency in regressing tumor growth, enhancing PD‐L1 responsive rate and prolonging survival of the B16F10 melanoma‐bearing mouse model. As a result, AOZNs provides a promising strategy for enhancing cancer immunotherapy.