Inspired Epigenetic Modulation Synergy With Adenosine Inhibition Elicits Pyroptosis And Potentiates Cancer Immunotherapy

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 gamma-oryzanol (Orz), the adenosine inhibitor alpha, beta-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.