Purpose <p>Tumor vaccines have been showing a relatively weak response rate in cancer patients. The combination of liposomal cancer vaccines with different kinds of agents could affect different arms of the immune system and/or tumor microenvironment (TME), potentially leading to more satisfactory immune responses. In this paper, we investigated effects of using a combination of liposomal cancer vaccines containing Pam₂- mucin 1 (MUC1) antigens, αGalCer and pan-histone deacetylase inhibitor (HDACi) SAHA with oncolytic peptide QR-KLU for cancer immunotherapy.</p> Methods <p>The physical properties of the SAHA contained liposomal vaccines was identified such as nanoparticle diameter and polydispersity index, zeta potential. Cell based assays were conducted to evaluate the cell toxicity of SAHA contained liposomal vaccines and lytic peptide QR-KLU. The in vivo assays with B16F10-MUC1 tumor-bearing mouse model were used to evaluate the tumor immune response and anti-cancer effect by the combination therapy of QR-KLU and SAHA contained liposomal vaccines.</p> Results <p>SAHA contained liposomal vaccines showed improved anti-cancer effect than liposomal vaccine alone on B16F10-MUC1 cells. The B16F10-MUC1 cells were sensitive to oncolytic peptide QR-KLU and were killed at low micromolar levels by QR-KLU. In order to test the enhanced tumor immune response by the combination therapy, we intratumorally injected lytic peptide QR-KLU into B16F10-MUC1 tumor-bearing mouse model, and then the mice were sequentially treated with SAHA@liposomal vaccines via intraperitoneal administration. The combined therapy demonstrated greatest reductions in tumor volume and systemic immune response compared with QR-KLU or SAHA@liposomal vaccines monotherapy. We further found the treatment was T-cell dependent, and also resulted in an abscopal effect as demonstrated by the regression of distal non-treated lesions.</p> Conclusion <p>Our research demonstrated that the combination of lytic peptide and SAHA@liposomal vaccines represents a new approach to cancer immunotherapy, which can be considered as a simple and potential method for simple but immunologically effective approach for the development of anti-MUC1 cancer vaccines.</p>