Photodynamic amplified immune checkpoint-blockade therapy of self-delivery bioregulator via epigenetic reprogramming

Photodynamic therapy (PDT) and immunotherapy have unique advantages for primary and metastatic tumor treatment. However, immunosuppressive tumor microenvironment (ITM) causes low immune responses and various degrees of therapeutic resistance. In this work, a self-delivery bioregulator (C-Moc) is developed for photodynamic amplified immune checkpoint-blockade (ICB) therapy by epigenetic reprogramming. To be spe-cific, carrier-free C-Moc is prepared by the self-assembly of chlorine e6 (Ce6) and mocetinostat (Moc) in the presence of DSPE-PEG2000 through electrostatic and hydrophobic interactions. Of note, nanosized C-Moc has an improved stability, cellular uptake and pharmacokinetics behaviors. Intravenously injected C-Moc prefers to accumulate at tumor site and then penetrate into tumor tissues upon light irradiation. Meanwhile, the initiated PDT would kill tumor cells for primary tumor inhibition and also induce immunogenic cell death (ICD) to activate antitumor immunity. More importantly, C-Moc is able to increase the expressions of MHC-I and PD-L1 to regulate ITM by epigenetic reprogramming, which would promote the recognition of immune system to MHC-I overexpressed tumor cells and enhance the ICB therapy of alpha-PD-L1. This photodynamic amplified ICB therapy of C-Moc shows a great superiority over the single treatment on primary and distant tumor suppression.