<i>In vivo</i>, combined EZH2 inhibition and DOX significantly suppressed tumor growth, while pH-responsive liposomal delivery further enhanced antitumor efficacy and reduced systemic toxicity.<h4>Conclusion</h4>EZH2 is a critical determinant of DOX resistance in breast cancer by sustaining DNA damage tolerance and metabolic homeostasis. Here, EZH2 is linked to breast cancer.