Cutting the root:the next generation of T cells engagers against cancer stem cells to overcome drug resistance in triple-negative breast cancer

Triple-negative breast cancer(TNBC)is the most difficult type of breast cancer to treat.TNBC is defined by the lack of expression of three receptors:estrogen receptor(ER);progesterone receptor(PR);and human epidermal growth factor receptor 2(HER2).Chemotherapy is currently first-line treatment for TNBC;however,due to the high heterogeneity of TNBC,most patients eventually develop chemotherapy resistance,which is associated with a poor prognosisl-2.Emerging immune checkpoint blockade(ICB)therapies have been shown to have promising therapeutic efficacy in treating solid tumors.A phase III clinical trial reported that the combination of ICB and chemotherapy lengthened progression-free survival in patients with metastatic PD-L1+TNBC3;however,most patients had primary resistance or acquired resistance to ICB.Thus,the intrinsic mechanisms underlying ICB resistance are still under investigation4.

Mitochondria-targeted nanoparticles overcome chemoresistance via downregulating BACH1/CD47 axis in ovarian carcinoma

The platinum-based chemotherapy is a routine strategy for the treatment of ovarian cancer,while it is prone to chemoresistance in clinical,which hinders the treatment.Therefore,it is urgently needed to elucidate the underlying mechanism of drug resistance and form the appropriate strategy.The sequencing results showed that cisplatin(DDP)resistant ovarian cancer overexpressed BTB and CNC homology 1(BACH1),and up-regulated the“don’t eat me”signal CD47.We identified that hemin,a BACH1 inhibitor,could effectively down-regulate BACH1 and simultaneously inhibit CD47.Moreover,hemin has a synergistic effect with DDP.We designed a pH-responsive nanoparticle(H/D@FA-CaP-NPs)in which folic acid(FA)ensured targeting of ovarian cancer cells,while hemin inhibited BACH1 as well as down-regulated CD47,achieving the promotion of apoptosis of tumor cells and inducing phagocytosis of tumors by macrophages.Moreover,hemin has a synergistic effect with DDP to promote apoptosis of tumor cells.Structurally,hemin and DDP was encapsulated within hydrophobic 1,2-distearoyl-sn-glycero-3-phosphoethanolamine(DSPE)to form a tight core,and hydrophilic polyethylene glycol 2000(PEG2000)and calcium phosphate(CaP)formed the outside shell,and FA was modified on the surface of nanoparticles.In terms of function,(a)FA enhanced the active targeting of nanoparticles to tumors;(b)NPs targeted mitochondria to induce reactive oxygen species(ROS)production;(c)hemin encapsulated in nanoparticles could specifically target BACH1,thereby down regulating CD47;(d)hemin had a synergistic effect with DDP,thus augmenting the chemotherapy.Altogether,mitochondria-targeted nanoparticles H/D@FA-CaP-NPs promoted tumor apoptosis and mobilized phagocytosis to treat tumor,providing a novel scheme for clinical treatment of cisplatin-resistant ovarian carcinoma.

Local delivery of arsenic trioxide nanoparticles for hepatocellular carcinoma treatment

Hepatocellular carcinoma(HCC)is a malignancy with a poor prognosis.Surgery combined with chemotherapy has been recommended as a curative regimen for HCC.Nevertheless,the anticancer mechanisms of chemicals in hepatocellular carcinoma remain unclear.Pyroptosis is a type of programmed necrosis,and its mechanism in hepatocellular carcinoma is poorly understood.The efficacy and mechanism of arsenic trioxide nanoparticles in the treatment of HCC were explored in this research.Arsenic trioxide alone and arsenic trioxide nanoparticles were conveniently administered to mice intratumorally using a needle.Compared with As_(2)O_(3),As_(2)O_(3)nanoparticles(As_(2)O_(3)-NPs)showed better inhibition,promoted greater LDH release,and induced cell morphology indicative of pyroptosis in vitro.Compared with the free drug,As_(2)O_(3)-NPs increased GSDME-N expression and decreased Dnmt3a,Dnmt3b,and Dnmt1 expression in Huh7 cells.In vivo,As_(2)O_(3)-NPs induced a significant decrease in the expression of Dnmt3a,Dnmt3b and Dnmt1,but significantly upregulated the expression of GSDME-N(gasdermin E(GSDME)was originally found to be related to deafness;recently,it has been defined as a gasdermin family member associated with pyroptosis).As_(2)O_(3)-NPs inhibited tumor growth more strongly than As_(2)O_(3)or control,a finding likely attributed to the downregulation of PCNA and DNMT-related proteins and the upregulation of GSDME-N.