Autophagy Inhibitor Synergizes With Electrodynamic Therapy To Regulate Tumor Immune Microenvironment For Tumor Ablation

Electrodynamic therapy(EDT),as an emerging type of dynamic therapy,which can generate infinite reactive oxygen species(ROS)under the external electric field for its raw material water abundant exited in organism.Different from other dynamic therapies,EDT not only overcomes the problem of limited ROS generation efficiency,but also relief the hypoxia in the tumor region.However,previous studies evidence that EDT alone is difficult to achieve long-term tumor inhibition effect in the tumor immunosuppressive microenvironment(TIME),facing the risk of tumor recurrence.To date,only few studies have combined EDT with other therapies,such as starvation therapy,chemotherapy or immunosuppressor to combat tumor recurrence.There is an urgent need to raise new strategies to prevent tumor metastasis and recurrence.The protective autophagy in tumor cells induced by the elevated level of oxidative stress during the dynamic therapy is another obstacle for cancer therapy.Tumor cells may digest the damaged proteins and organelles to relief the toxic damage caused by ROS.Moreover,the degradation products in autophagy process can also provide energy for cancer cells,thus protecting tumor cells from oxidative stress damage.Even worse,it is possible to obtain the opposite therapeutic effect in treatment.Therefore,it is a good choice to improve antitumor effect for nanomaterials via interfering autophagy process.Chloroquine(CQ),a classic autophagy inhibitor that efficiently blocks autophagic flux,also can be used as an immunomodulator by re-educating M2tumor-associated macrophages(TAMs)polarizing to Ml-TAMs.Therefore,porous Pt-Ir NPs incorporated with CQ(Pt-Ir-CQ NPs)are constructed to improve the therapeutic effect of EDT by inhibiting autophagy and re-educating macrophage polarization.On the one hand,CQ blocks the protective autophagy induced by EDT,causing an enhanced killing effect on tumor cells.On the other hand,CQ re-educates M2-TAMs polarize to MI-TAMs,which combines with immunogenic cell death(ICD)effect induced by EDT to achieve synergistic immunotherapy.In vivo and in vitro results suggest that the combination therapy can play a long-term inhibitory effect on tumors by regulating the TIME and achieving enhanced EDT therapy.Our study provides a new strategy for EDT synergistic therapy to effectively ablate large tumors.