Carrier-free Nanomedicine With Synergistic Effect For Enhancing Tumor Immunotherapy

Cancer remains by far one of the greatest threats to human health.People have been devoting themselves to exploring various treatment strategies to overcome cancer.In the past few decades,the development of immunotherapy has changed the model of cancer treatment.Immunotherapy is a therapeutic method to activate the whole immune system to attack tumor cells,to treat tumor,to prevent tumor recurrence and metastasis,and finally to cure tumor.However,most patients do not respond well to treatment,mainly because the tumor has a variety of immune escape mechanisms to evade the monitoring and elimination of the immune system.Recent studies have shown that photodynamic therapy can make tumor cells produce a large amount of reactive oxygen species,cause immunogenic cell death effect,and improve the sensitivity of tumors to immunotherapy.However,due to the low delivery efficiency of photosensitizers and the limitations of various defense mechanisms closely related to glutamine metabolism in the tumor microenvironment,photodynamic therapy alone can only play a limited role in immunotherapy.For example,reactive oxygen species produced by photodynamic therapy can be rapidly eliminated by high levels of glutathione(GSH)in tumor cells,thus weakening the immunogenic cell death effect caused by photodynamic therapy.In addition,immunosuppressive tumor microenvironment(ITM)is conducive to the infiltration of immunosuppressive cells,which inhibits the effect of immunotherapy induced by photodynamic therapy alone.Therefore,a simple strategy that can simultaneously destroy the redox homeostasis in tumor cells and reverse the tumor immunosuppressive microenvironment is very important to enhance the immunotherapeutic effect of photodynamic therapy.Inspired by this,a carrier-free immunotherapy nano-drug with dual synergistic effect was prepared by self-assembly of glutaminase inhibitor compound 968(C968)and photosensitizer chlorin e6,named C9SN.Because carrier-free C9SN nanoparticles are only composed of active drugs,they have higher loading and encapsulation efficiency.In addition,compared with free drugs,C9SN nanoparticles can accumulate more in tumor sites and be absorbed by tumor cells.Generally speaking,C9SN nanoparticles significantly improve the delivery efficiency of photosensitizer Ce6.After C9SN nanoparticles were delivered to the tumor site,the glutaminase inhibitor C968 in C9SN nanoparticles prevented the elimination of reactive oxygen species produced by photodynamic therapy by glutathione by inhibiting cell glutamine metabolism,magnified intracellular oxidative stress,led to severe cell death,and enhanced immunogenic cell death and immunogenicity.Since then,the new antigen produced by the enhanced immunogenic cell death effect promotes the maturation of dendritic cells in mouse lymph nodes,thereby recruiting and activating cytotoxic T lymphocytes.At the same time,C9SN nanoparticles reshape the immunosuppressive tumor microenvironment by blocking glutamine metabolism,polarizing antiinflammatory M2 tumor-associated macrophages into pro-inflammatory M1 tumorassociated macrophages,thus further recruiting and activating cytotoxic T lymphocytes.Finally,C9SN nanoparticles effectively inhibit the growth of primary and distant tumors.This strategy of "killing two birds with one stone" will help to enhance tumor immunogenicity and alleviate tumor immunosuppression,so as to improve the immunotherapeutic effect of photodynamic therapy.