Nucleus-targeted silencing of EPIC1 expression as an epigenetic strategy to modulate tumor immune microenvironment and potentiate cancer immunotherapy.

Epigenetic regulation plays a pivotal role in cancer development and progression, in which long non-coding RNAs (lncRNAs) have emerged as one of the most important epigenetic regulators because of their ability to promote immune evasion and tumor progression. Therefore, targeted regulation of lncRNA expression could be a promising epigenetic strategy for enhanced cancer therapy, which however remains challenged due to the localization of lncRNAs in various membrane-bound organelles (e.g., nucleus and mitochondrion). We herein developed a nucleus-targeted RNA interfering (RNAi) nanoplatform for specific silencing of epigenetically induced MYC interacting lncRNA 1 (EPIC1), a nucleus-localized oncogenic lncRNA that is negatively correlated with antitumor immune response and prognosis of breast cancer (BCa) patients. Using BCa orthotopic and metastatic tumor models, we demonstrated this RNAi nanoplatform could efficiently silence EPIC1 expression in BCa cells and significantly inhibit BCa tumor growth. Mechanism study shows this EPIC1 silencing could block the function of histone methyltransferase EZH2 to catalyze the methylation of lysine 27 on histone H3 (H3K27me3) at the promoter region of its target genes, which could not only directly inhibit BCa tumor growth by up-regulating tumor suppressor genes (e.g., BAX and TP53), but also enhance the expression of immunoactive genes (e.g., MHC-I, IFN-β, CXCL9, and CXC10) to potentiate BCa immunotherapy. Our findings indicate that EPIC1 silencing with the nucleus-targeted RNAi nanoplatform could be a promising epigenetic strategy for effective cancer therapy.