Construction And Activity Study Of A Dual Immune Checkpoint Inhibitors Synergistic Photothermal Nanosystem For Triple-Negative Breast Cancer

Triple-negative breast cancer(TNBC)is a malignant tumor with high invasion and metastasis characteristics.Due to the lack of estrogen receptor,progesterone receptor and expression of human epidermal growth factor receptor 2(HER2),as well as the heterogeneous pathological and molecular characteristics,its treatment remains a major challenge in oncology.There is an urgent need to develop efficient and specific therapies.As the most immunogenic subtype of breast cancer and rich in TILs and PD-L1 protein expression,TNBC may benefit from immune checkpoint inhibitor(ICI)therapy.However,the up-regulation of various immunosuppressive cells and multiple immune checkpoints in the tumor microenvironment limit the effect of single ICI in TNBC.The overexpression of PD-L1 and CD47 in TNBC means that both innate and adaptive immunity are suppressed in the tumor microenvironment.Awakening both of the innate and adaptive immune responses with the ICIs of PD-1 and CD47,while reversing the function of immunosuppressive cells such as M2 tumor-associated macrophages(TAMs)in the tumor microenvironment raises a tantalizing prospect in the treatment of TNBC.In our work,we constructed a stimuli-responsive multifunctional anti-TNBC nanoplatform(ZIF-PQ-PDA-AUN),which organically synergizes photothermal and dual ICI therapy.ZIF-PQ-PDA-AUN ablated tumor cells through photothermal therapy,and at the same time promoted the TILs inside the tumor;AUNP-12 and PQ912 restored the innate and adaptive immune responses in the tumor by cutting off PD-L1 and CD47 signals,and further enhanced the phagocytosis of M1 type TAMs while inducing the polarization of tumor-promoting M2 type TAMs to anti-tumor M1 type TAMs.Compared with a single ICI immunotherapy,the nanoplatform presented a stronger anti-tumor immune effect and lower autoimmune side effects,which may provide a new strategy for the treatment of TNBC.