All in all, with a controlled release of siRNA-PD-L1 and SAHA spontaneously into the cytoplasm of tumor cells, siRNA@PPDS demonstrated an outstanding therapeutic effect on mice bearing melanoma in vitro and in vivo, revealing that by comprehensively activating the immune system, lysosome activable polymeric vorinostat encapsulating PD-L1KD for the combination therapy of PD-L1-KD and HDACIs can be an effective strategy to reverse the unresponsiveness of immune checkpoint inhibitors and a promising treatment to inhibit tumor growth and metastasis in clinic. This evidence concerns the gene CD274 and neoplasm.