Activatable Nanomedicine For Synergistic Treatment Of Cancer Immunotherapy

Cancer immunotherapy is an emerging therapeutic strategy that modulates the immune system to fight against cancer.Although several immunotherapeutic agents have been used to treat cancer clinically,the presence of "cold" tumors in some cases has led to low response rates to immunotherapy.In addition,some immune-related adverse events appeared,leading to a great challenge for immunotherapy.Nanodrugs offer an opportunity to promote the clinical transformation of immunotherapy,due to its specific advantages in accumulation and release at tumors site.Nanomedicines accumulate in tumors through the EPR effect and specific receptors based active targeting on the surface of tumor cells.The accumulation of nanomedicines improves its efficiency and reduces the system toxicity.Nano-system control the release of drugs and relieve the tumor immunosuppressive microenvironment.Traditional chemotherapy,radiotherapy and phototherapy could be combined with immunotherapy effectively with the help of nanomedicines.Immunogenic death(ICD)of tumor cells induced by these traditional methods stimulate a tumor specific immune response.Immunotherapies are expected to regulate the immunosuppressive microenvironment.After removing the primary tumors,combination therapies eliminate the remained tumor cells and prevent tumor recurrence or metastasis.Herein,we modified PEG with PD-L1 inhibitor(BMS-1)through a reversible DA reaction and further synthesized I-Pt NPs with PEG as capping agents.Under NIR laser irradiation,I-Pt NPs ablate tumor cells and release the antigens.At the same time,the temperature on the surface of I-Pt NPs reaches the temperature for reverse DielsAlder reaction.BMS-1 is released and maleimide(Mal)is exposed.I-Pt NPs serve as adjuvant and promote the maturation of DCs.At the same time,Mal on the surface of Pt NPs capture the antigens released after photothermal therapy(PTT).The adjuvant function of I-Pt NPs promotes antigen presentation by DCs to T cells and enhances the immune response.The released BMS-1 binds the PD-L1 receptors and relieves the immunosuppressive tumor microenvironment and further augments the immune response.Meanwhile,thermosensitive liposomes were chosen to carry IR780,oxaliplatin(OXA)and BMS-1.PTT and OXA produce a synergistic ICD effect and expose antigens,eliciting a tumor specific immune response finally.PTT temperature was same as the phase transition temperature of liposomes.OXA and BMS-1 can be released after PTT.The released BMS-1 further increases T cell penetration and enhances the efficiency of immunotherapy.Then,OXA was modified with hydrophilic and hydrophobic group.The obtained OXA based polymer was then assembled into nano-micelles and DHA was loaded in cores,which could be accumulated at the tumor site.Under the acidic conditions,the BMS-1 was released due to the broken of pH responsive bond,which would bind with the PD-L1 receptor on the surface of tumor cells.The nanostructure did not change after the release of BMS-1 and continue to be endocytosis.OXA and DHA are released under the GSH environments in tumor cells,resulting in enhanced ICD of tumor cells.ICD and BMS-1 could synergistically eliminate tumor tissue and effectively inhibit tumor growth with the help of enhanced tumor specific immune response.