Combination of chemotherapy with gene therapy is a promising strategy for cancer treatment.The aim of the current study is to simultaneously deliver the chemotherapeutic drug and gene (DNA) to the same tumor cell for better anti-tumor ability.We constructed an innovative cationic polymer poly (ethylene glycol)-g-linerpoly(ethyleneimine)-g-poly(ε-caprolactone) (mPEG-LPEI-PCL, PLP) as gene/drug co-delivery carrier.This PLP polymer could encapsulate drug and condense DNA simultaneously into a suitable size particle, with possible low cytotoxicity, high gene transfection efficiency and sustained drug release ability.In the current study, pcDNA3.1/ calreticulin (CRT) recombinant plasmid and chemotherapy drug Doxorubicin (DOX) were encapsulated into this novel PLP polymer simultaneously.Our results showed that the systemic administration of pcDNA-CRT plus DOX polymer induced a significant tumor suppression of mouse melanoma transplanted with B16F10 cells.We further demonstrated that the activation of tumor immune response of the mice was a result of overexpression of CRT protein, which was transfected by pcDNA3.1/CRT recombinant plasmid and further induced by co delivered of DOX.Then a synergistic enhancement of tumor immunity was triggered, resulting in more macrophages infiltration in tumor tissue and enhance tumor cell phagocytosis.Our results suggested that this novel multifunctional PLP is a promising carrier for the delivery of both gene and chemotherapeutic drugs together to achieve a synergistic antitumor effect.