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Graphical Abstract Abbreviations CircRNA Circular RNA CRC Colorectal cancer DNMT DNA methyltransferase LIF Leukemia inhibitory factor LncRNA Long non-coding RNA MiRNA MicroRNA NcRNA Non-coding RNA NK Natural Killer cell PiRNA PIWI-interacting RNA SiRNA Small interfering RNA TME Tumor microenvironment DNMT DNA methyltransferase MDR1 Multidrug resistance 1 HDACs Histone deacetylases PRC2 Polycomb repressive complex 2 NEAT1 Nuclear paraspeckle assembly transcript 1 Introduction Epigenetic modifications have emerged as key players in the unfathomable complexities of cancer biology, driving an astounding degree of heterogeneity and leading to the frustrating challenge of drug resistance [1,2]