Immune evasion and metastasis are the leading causes of poor prognosis in triple-negative breast cancer treatment. Since current standard immunotherapies have limited efficacy due to immunologically cold microenvironment, it is crucial to explore new strategies to sensitize anticancer immune response. In this study, it is found that incorporating β-lapachone-based oxidation therapy with CUDC101-initiated epigenetic regulation results in synergistic antitumor effects and potent immune activation. To co-deliver these two hydrophobic drugs, IR783 with cyanine structure serves as the stabilizer to form a nanoformulation based on small molecule self-assembly. Such IR783-stabilized nanodrugs can not only lead to cancer cell apoptosis through HDAC inhibition-enhanced oxidation therapy but also cooperatively induce immunogenic cell death and promote pro-inflammatory cytokine gene expression to reshape immunosuppressive microenvironment. Besides, nanodrugs can inhibit both primary and distant tumor growth effectively by elevating systemic anticancer immunity. This study provides a promising approach to synergize oxidation therapy with epigenetic modulation for safe and efficient breast cancer immunotherapy.