Strict conditions such as hypoxia, overexpression of glutathione (GSH), and high concentration of hydrogen peroxide (H2O2) in the tumor microenvironment (TME) limit the therapeutic effects of reactive oxygen species (ROS) for photodynamic therapy (PDT), chemodynamic therapy (CDT), and sonodynamic therapy (SDT). Here we fabricated a biocatalytic Janus nanocomposite (denoted as UPFB) for ultrasound (US) driven SDT and 808 nm near-infrared (NIR) light mediated PDT by combining core–shell–shell upconversion nanoparticles (UCNPs, NaYF4:20%Yb,1%Tm@NaYF4:10%Yb@NaNdF4) and a ferric zirconium porphyrin metal organic framework [PCN-224­(Fe)]. Our design not only substantially overcomes the inefficient PDT effect arising from the inadequate Förster resonance energy transfer (FRET) process from UCNPs (donor) to MOFs (acceptor) with only NIR laser irradiation, but also promotes the ROS generation via GSH depletion and oxygen supply contributed by Fe3+ ions coordinated in UPFB as a catalase-like nanozyme. Additionally, the converted Fe2+ from the foregoing process can achieve CDT performance under acidic conditions, such as lysosomes. Meanwhile, UPFB linked with biotin exhibits a good targeting ability to rapidly accumulate in the tumor region, verified by fluorescence imaging and T 2-weighted magnetic resonance imaging (MRI). In a word, it is believed that the synthesis and antitumor detection of UPFB heterostructures render them suitable for application in cancer therapeutics.

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The therapeutic effect of traditional chemodynamic therapy (CDT) agents is severely restricted by their weakly acidic pH and glutathione (GSH) overexpression in the tumor microenvironment. Here, fusiform-like copper­(II)-based tetrakis­(4-carboxy phenyl)­porphyrin (TCPP) nanoscale metal–organic frameworks (nMOFs) were designed and constructed for the first time (named PCN-224­(Cu)-GOD@MnO2). The coated MnO2 layer can not only avoid conjugation of glucose oxidase (GOD) to damage normal cells but also catalyzes the generation of O2 from H2O2 to enhance the oxidation of glucose (Glu) by GOD, which also provides abundant H2O2 for the subsequent Cu+-based Fenton-like reaction. Meanwhile, the Cu2+ chelated to the TCPP ligand is converted to Cu+ by the excess GSH in the tumor, which reduces the tumor antioxidant activity to improve the CDT effect. Next, the Cu+ reacts with the plentiful H2O2 by enzyme catalysis to produce a toxic hydroxyl radical (•OH), and singlet oxygen (1O2) is synchronously generated from combination with Cu+, O2, and H2O via the Russell mechanism. Furthermore, the nanoplatform can be used for both TCPP-based in vivo fluorescence imaging and Mn2+-induced T 1-weighted magnetic resonance imaging. In conclusion, fusiform-like PCN-224­(Cu)-GOD@MnO2 nMOFs facilitate the therapeutic efficiency of chemodynamic and starvation therapy via combination with relief hypoxia and GSH depletion after acting as an accurate imaging guide.

Recent studies have shown that long non-coding RNAs (lncRNAs) are involved in a variety of biological processes and diseases in humans, including cancer. Our study serves as the first comprehensive analysis of lncRNA TP73-AS1 in esophageal cancer. We utilized a lncRNA microarray to analyze the expression profile of lncRNAs in esophageal squamous cell carcinoma. Our results show that lncRNA TP73-AS1 and BDH2 levels are generally upregulated in esophageal cancer tissues and are strongly correlated with tumor location or TNM stage in clinical samples. LncRNA TP73-AS1 knockdown inhibited BDH2 expression in EC9706 and KYSE30 cells, whereas BDH2 knockdown repressed esophageal cancer cell proliferation and induced apoptosis via the caspase-3 dependent apoptotic pathway. Overexpression of BDH2 in lncRNA TP73-AS1 knockdown cells partially rescued cell proliferation rates and suppressed apoptosis. In mouse xenografts, tumor size was reduced in lncRNA TP73-ASI siRNA-transfected tumors, suggesting that downregulation of lncRNA TP73-AS1 attenuated EC proliferation in vitro and in vivo. In addition, BDH2 or lncRNA TP73-AS1 knockdown enhanced the chemosensitivity of esophageal cancer cells to 5-FU and cisplatin. Our results suggest that lncRNA TP73-AS1 may be a novel prognostic biomarker that could serve as a potential therapeutic target for the treatment of esophageal cancer.

Malignant Pleural Mesothelioma (MPM) is typically diagnosed 20–50 years after exposure to asbestos and evolves along an unknown evolutionary trajectory. To elucidate this path, we conducted multi-regional exome sequencing of 90 tumour samples from 22 MPMs acquired at surgery. Here we show that exomic intratumour heterogeneity varies widely across the cohort. Phylogenetic tree topology ranges from linear to highly branched, reflecting a steep gradient of genomic instability. Using transfer learning, we detect repeated evolution, resolving 5 clusters that are prognostic, with temporally ordered clonal drivers. BAP1/−3p21 and FBXW7/-chr4 events are always early clonal. In contrast, NF2/−22q events, leading to Hippo pathway inactivation are predominantly late clonal, positively selected, and when subclonal, exhibit parallel evolution indicating an evolutionary constraint. Very late somatic alteration of NF2/22q occurred in one patient 12 years after surgery. Clonal architecture and evolutionary clusters dictate MPM inflammation and immune evasion. These results reveal potentially drugable evolutionary bottlenecking in MPM, and an impact of clonal architecture on shaping the immune landscape, with potential to dictate the clinical response to immune checkpoint inhibition.