A Multifunctional Nanodrug Mediates Photodynamic Therapy And TAMs Arginine Metabolism Interference For Triple Negative Breast Cancer Treatment

Triple-negative breast cancer(TNBC)is a highly aggressive "cold" tumor with characters of ER(-),PR(-)and HER2(-).The prognosis is poor whatever surgery therapy or neoadjuvant chemo-radiotherapy.In recent years,tumor immunotherapy has brought about major innovations different from traditional tumor therapy.Although there is a series of representative immunotherapies,such as immune checkpoint blockade,tumor-specific vaccines and so on,only a few people benefit from this treatment due to individual differences and the presence of the immunosuppressive tumor microenvironment(ITM).An emerging body of research shows that immunogenic cell death(ICD)induced by chemotherapy drugs or physical therapy is an effective strategy to transform "cold" tumors into "hot" tumors.Photodynamic therapy(PDT)is a non-invasive treatment for inducing ICD by generating ROS to destroy tumor cells.However,it just stimulated the immune response,which can be doused by the immunosuppressive tumor microenvironment(ITM).ITM is composed of substantive tumor cells,tumor-infiltrating immune cells,extracellular matrix and so on.Owning to the metabolic dysregulation of tumor-infiltrating immune cells in ITM,these immune cells frequently suffer from impairment of their anti-tumor immune responses,facilitating tumor immune escape.This leads to a diminished immune response to the PDT-induced ICD.Tumor-associated macrophages(TAMs)are the most abundant immune cells in solid tumor.TAMs can be polarized into two distinct types,namely,tumor-suppressive M1 macrophages and tumor-promoting M2 macrophages.They are two alternate states of macrophage,which can be driven by two completely opposite metabolic pathways of L-Arginine(L-Arg)in macrophages.Extensive research shows that L-Arg can be catalyzed into nitric oxide(NO)through nitric oxide synthase(iNOS)of M1 and also decomposed into polyamines by arginase-1(ARG-1)of M2.TAMs are more likely to polarize toward M2 because the ARG-1 pathway in M2 may competitively inhibited the way of iNOS in M1 by arginine deprivation.Therefore,remodeling ITM by regulating the L-Arg metabolic pathway of macrophages is a promising target to enhance antitumor immunity response.Given the above consideration,a multifunctional nanodrug(named as HN-HFPA)was developed for PDT trigger ICD and remolding ITM.Herein,we utilize pH-dissolvable ZIF-8 as a self-sacrificial template,guiding the photosensitizer TCPP and Fe3+ coordinating into hollow metal-organic framework(HFP).L-Arg,a macrophage metabolism amino acid playing a crucial role in modulating immune responses,can be effectively loaded in the cavity of HFP by electrostatic adherence.Meanwhile,HN-HFPA was constructed by decorating with hyaluronic acid-conjugated the ARG-1 inhibitor L-norvaline(L-Nor)on HFPA.HN-HFPA was specifically accumulated in 4T1 tumor tissues due to the targeting CD44 receptor property of HA.GSH-dissociated HN-HFPA will fast release L-Arg and L-Nor under GSH-rich tumor microenvironment and trigger ICD by TCPP-mediated photodynamic therapy.L-Arg can further react with ROS to generate NO,which can kill tumor cell enhancing PDT.what’s more,NO can be used for ultrasound imaging of tumors to detect tumors in real time.when the ICD recruits T cells to trigger the anti-tumor immune response,the L-Nor,an inhibitor of ARG-1 regulating the arginine metabolism of tumor-associated macrophages in the tumor immunosuppression microenvironment,can reeducate TAMs from M2 to M1 enhancing the anti-tumor immune response of TNBC.