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To modulate immunosuppressive tumor microenvironment and overcome the cancerous resistance to chemotherapy for effectively tumor killing, the novel nano-assemblies were developed for tumor chemo-immunotherapy. The broken of polydopamine (PDA) sensitized the tumor cells for reducing the tumor resistance against doxorubicin (DOX) and effectively induced immunogenic tumor cell death (ICD), respectively. The neo-antigen generated by the ICD effect in situ could be greatly presented by the simvastatin (SIM) activated dendritic cells (DCs) for specific T cells production. [Display omitted] • To modulate immunosuppressive tumor microenvironment and overcome the cancerous resistance to chemotherapy for effectively tumor killing, the SIM@NPs-PDA/DOX nano-assemblies, was developed to sequentially delivery doxorubicin (DOX), polydopamine (PDA) and simvastatin (SIM) for tumor chemo-immunotherapy. • The nano-assemblies were made of two kinds of lipopolymer, PDA-conjugated DSPE-PEG and DOX-absorbed DSPE-PEG. The SIM was subsequently loaded into the hydrophobic core during the self-assembling process. • The PDA was found the function of sensitizing the tumor cells for reducing the tumor resistance against DOX by deactivating AKT signaling pathway. • The neo-antigen generated by the immunogenic tumor cell death (ICD) effect in situ could be greatly presented by the SIM activated dendritic cells (DCs) for specific T cells production. The combination of chemotherapy and immunotherapy is the first line treatment for many cancers. However, resistance to chemotherapy is a common phenomenon, as well as the failure of antigen presentation and T cell infiltration are the fundamental obstacle for effective combined oncotherapy. Many studies have clarified the importance of increased reactive oxygen species (ROS) in reducing multidrug resistance (MDR) by disrupting oxidative balance and activating signaling pathways. Here, to modulate immunosuppressive tumor microenvironment (TME) and overcome the cancerous resistance to chemotherapy for effectively tumor killing, the SIM@NPs-PDA/DOX nano-assemblies, was developed to sequentially delivery doxorubicin (DOX), polydopamine (PDA) and simvastatin (SIM) for tumor chemo-immunotherapy. When the nano-assemblies penetrated into tumor TME, PDA and DOX were released by the hypoxia and low acid condition of TME, which sensitized the tumor cells for reducing the tumor resistance against DOX and effectively induced immunogenic tumor cell death (ICD), respectively. The neo-antigen generated by the ICD effect in situ could be greatly presented by the SIM activated dendritic cells (DCs) for specific T cells production. Simultaneously, the released DOX was also expected to kill tumor-associated macrophages (TAMs) for enhancing the specific T cell infiltration. In B16F10 and MCF-7 tumor cells with acquired drug resistance and relevant tumor models, the designed nano-assemblies showed powerful anti-tumor effects by reducing MDR, killing cancer cells and TAMs, promoting CD8+ T cells activation and infiltration. This study provides a novel nano-assemblies for effective onco-immuno-chemotherapy by overcoming cancer multidrug resistance and immuno-depletion. [ABSTRACT FROM AUTHOR]