A metabolic intervention strategy to break evolutionary adaptability of tumor for reinforced immunotherapy

The typical hallmark of tumor evolution is metabolic dysregulation.In addition to secreting immunoregulatory metabolites,tumor cells and various immune cells display different metabolic pathways and plasticity.Harnessing the metabolic differences to reduce the tumor and immunosuppressive cells while enhancing the activity of positive immunoregulatory cells is a promising strategy.We develop a nanoplatform(CLCeMOF)based on cerium metal-organic framework(CeMOF)by lactate oxidase(LOX)modification and glutaminase inhibitor(CB839)loading.The cascade catalytic reactions induced by CLCeMOF generate reactive oxygen species“storm”to elicit immune responses.Meanwhile,LOX-mediated metabolite lactate exhaustion relieves the immunosuppressive tumor microenvironment,preparing the ground for intracellular regulation.Most noticeably,the immunometabolic checkpoint blockade therapy,as a result of glutamine antagonism,is exploited for overall cell mobilization.It is found that CLCeMOF inhibited glutamine metabolism-dependent cells(tumor cells,immunosuppressive cells,etc.),increased infiltration of dendritic cells,and especially reprogrammed CD8^(+)T lymphocytes with considerable metabolic flexibility toward a highly activated,long-lived,and memory-like phenotype.Such an idea intervenes both metabolite(lactate)and cellular metabolic pathway,which essentially alters overall cell fates toward the desired situation.Collectively,the metabolic intervention strategy is bound to break the evolutionary adaptability of tumors for reinforced immunotherapy.

Dendritic nanomedicine enhances chemoimmunotherapy by disturbing metabolism of cancer-associated fibroblasts for deep penetration and activating function of immune cells

Inefficient drug penetration hurdled by the stroma in the tumor tissue leads to a diminished therapeutic effect for drugs and a reduced infiltration level of immune cells.Herein,we constructed a PEGylated dendritic epirubicin(Epi)prodrug(Epi-P4D)to regulate the metabolism of cancer-associated fibroblasts(CAFs),thus enhancing Epi penetration into both multicellular tumor spheroids(MTSs)and tumor tissues in mouse colon cancer(CT26),mouse breast cancer(4T1)and human breast cancer(MDA-MB-231)models.Enhanced cytotoxicity against CT26 MTSs and remarkable antitumor efficacy of Epi-P4D were ascribed to reduced fibronectin,α-SMA,and collagen secretion.Besides,thinning of the tumor tissue stroma and efficient eradication of tumor cells promoted the immunogenic cell death effect for dendritic cell(DC)maturation and subsequent immune activation,including elevating the CD4^(+)T cell population,reducing CD4^(+)and CD8^(+)T cell hyperactivation and exhaustion,and amplifying the natural killer(NK)cell proportion and effectively activating them.As a result,this dendritic nanomedicine thinned the stroma of tumor tissues to enhance drug penetration and facilitate immune cell infiltration for elevated antitumor efficacy.

BaTiO_(3)@Au nanoheterostructure suppresses triple-negative breast cancer by persistently disrupting mitochondrial energy metabolism

Abnormal metabolism has become a potential target for highly malignant and invasive triple-negative breast cancer(TNBC)due to its relatively low response to traditional therapeutics.The existing metabolic interventions demonstrated unsatisfactory therapeutic outcomes and potential systemic toxicity,resulting from the metabolic instability and limited targeting ability of inhibitors as well as complex tumor microenvironment.To address these limitations,here we developed a robust pyroelectric BaTiO_(3)@Au core–shell nanostructure(BTO@Au)to selectively and persistently block energy generation of tumor cells.Stimulated by near-infrared(NIR)laser,the Au shell could generate heat to activate the BaTiO_(3)core to produce reactive oxygen species(ROS)regardless of the constrained microenvironment,thus prominently inhibits mitochondrial oxidative phosphorylation(OXPHOS)and reduces ATP production to induce TNBC cell apoptosis.The therapeutic effects have been well demonstrated in vitro and in vivo,paving a new way for the development of metabolic interventions.