Nano-delivery System-based Photothermal Therapy Combined With Immune Checkpoint Blocking Anti-tumor Research

Cancer is one of the major causes of death.Cancer immunotherapies have demonstrated promising clinical responses in recent years and provide a new strategy against cancer beyond traditional treatment approaches,such as surgery,chemotherapy and radiotherapy.Of particular interest for the immunotherapy is the blockade of immune checkpoint which targets regulatory pathways in T cells.However,immune checkpoint blockade therapy is not generally curative,and combination with other cancer treatments approaches will be promising for improved cancer immunotherapy.Photothermal therapy(PTT)to treat local tumors using photothermal agents xmder laser irradiation has been widely studied recently.PTT can directly kill tumor cells and the resulted tumor-derived antigens can recruit and activate antigen-presenting cells in the ablated txunor site,thus inducing the antigen-specific antitumor immune response.In this study,multifunctional nanocomplexes are designed for the co-delivery of pohotosensitizer and immune checkpoint regulators,which may possess an untapped potential to achieve the synergistic/combined effect of photothermal therapy and immunotherapy.Part ?:Here,we designed a multi-combination immunotherapy including PTT,indoleamine-2,3-dioxygenase(IDO)inhibition and programmed cell-death ligand 1(PD-Ll)blockade for synergistically enhancing anti-tumor immune responses.We prepared the reduced graphene oxide(rGO)nanoconjugates loaded with IDO inhibitors,and the surface was modified with folic acid to enhance the accumulation of tumor sites.The multi?functional nanoparticles could directly kill tumor cells under laser irradiation and activate anti-tumor immune response.In vivo experiments revealed that IDO inhibition combined with PD-L1 blockade enhanced the infiltration of tumor infiltrating lymphocytes(TILs)including CD45~+leukocytes,CD4~+T cells,CD8~+T cells and NK cells,and also inhibited the immunosuppressive activity of regulatory T cells(Treg)as well as increased the production of interferon y(INF-y).The results mentioned above showed that the combination therapy of PTT,IDO inhibition and PD-L1 blockade could effectively inhibit tumor growth,which further demonstrated the synergistic anti-tumor immunity by targeting multiple anti-tumor immune pathways.Part ?:Here,a tumor microenvironment-responsive dual-drug loaded nanoparticle is developed for combination therapy of photothermal killing and IDO Inhibition.This carrier-free nanodrugs were co-self-assembled with indocyanine green(ICG)and epacadostat(IDOi)through the collaborative interactions(electrostatic,?-? stacking,and hydrophobic interactions)between drug molecules.When exposed to the tomor microenvironment,the shell-core structure of the nanodrugs disintegrated,and subsequently resulted in the production of more smaller-sized particulate aggregates,suggesting the potential capability of the nanodrugs to deliver drugs into deep tumor cells.In vivo anti-tumor efficacy studies showed that the nanodrugs-mediated PTT can effectively inhibit tumor growth and activate anti-tumor immune responses.PTT treatment with the combination of IDO inhibition enhanced the infiltration of TILs in the tumor,including CD45~+leukocytes,CD4~+T cells,CD8~+T cells,B cells and NK cells,and also inhibited the immunosuppressive activity of Treg.These results demonstrated that the nanodrugs-based PTT treatment with the combiantion of IDO inhibition could effectively inhibit the growth of irradiated tumors,efficiently promote the activation of antigen presenting cells and trigger antitumor immune responses.In summary,we have successfully constructed two kinds of multifunctional nanodrugs for the combination of photothermal therapy and immune checkpoint blockade therapy.In the present works,multifunctional nanocomplexes are designed for the co-delivery of pohotosensitizer and check point blockers,which may possess an untapped potential to achieve the synergistic/combined effect of photothermal therapy and immune therapy.Strong antitumor effectiveness,combined with enhanced immune responses,would seem to justify further development of the multifunctional nanocomplexes-based photothermal-immuno cancer therapy as the new generation cancer therapeutic modality.