Reversing EZH2‐Mediated Epigenetic Silence with Photodynamic Polymeric Nanoparticles for Synergistically Enhanced Antitumor Immunotherapy

Abstract Endogenous T cell activation relies on recognizing tumor‐specific antigens. However, tumor cells often alter phenotypes to evade immune surveillance, resulting in immune escape and drug resistance. Photodynamic therapy (PDT) activates anti‐tumor immune responses by generating reactive oxygen species, which induce endoplasmic reticulum stress and immunogenic cell death. The clinical application of PDT is limited by immunosuppressive tumor microenvironment. Notably, enhancer of zeste homolog 2 (EZH2) regulates expression of immune‐related genes in tumor and immune cells through H3K27 methylation. Consequently, targeting EZH2‐mediated epigenetic silence provides an effective strategy to enhance the anti‐tumor immune effect of PDT. In this study, a nano‐delivery system (NP2) is designed to demonstrate PDT and epigenetic reprogramming effects. NP2 can reverse epigenetic silence, enhance MHC‐I expression, and induce release of CXCL9‐10 via EZH2i. Meanwhile, NP2 has a significant effect on PDT, inducing endoplasmic reticulum stress that resulted in immunogenic cell death and subsequent activation of the immune cascade. In a mouse model of in situ breast cancer, the combination of PDT activation and epigenetic reprogramming through EZH2i showed synergistic effects on remolding, and triggering a robust anti‐tumor immune response in vivo. This study provides a novel idea for improving the immunosuppressive environment in clinical individualized immunotherapy.