Given the potent effects of DP-sHDL in boosting anti-tumor immunity and relieving immunosuppressive microenvironment, its efficacy in treating TNBC model mice was evaluated. Through a 3-dose regime, DP-sHDL inhibited the growth of tumors by 84% and significantly reduced tumor burden. In contrast, DOX was less effective and caused a progressive decline in body weight. Further biochemical assays revealed that the levels of AST, CREA, CK and LDH in DOX-treated mice were significantly higher than those receiving PBS. Accordingly, inflammatory cell infiltration, cell necrosis and local swelling were observed in the heart, liver and kidneys, respectively, in the DOX-injection group. With the same regime, no visible damage was monitored in the major organs in DP-sHDL group. Based on these findings, the long-term efficacy of D-sHDL, P-sHDL and DP-sHDL were further evaluated. DP-sHDL retarded the tumor growth, and prolonged the median survival time (MST) from 18 days (PBS-treated mice) to 35 days, without body weight loss. These results proved that DP-sHDL could reduce the toxicity of DOX and effectively inhibit tumor growth.