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Synovial Sarcomas (SS) are characterized by the presence of the SS18::SSX fusion gene, which protein product induce chromatin changes through remodeling of the BAF complex. To elucidate the genomic events that drive phenotypic diversity in SS, we performed RNA and targeted DNA sequencing on 91 tumors from 55 patients. Our results were verified by proteomic analysis, public gene expression cohorts and single‐cell RNA sequencing. Transcriptome profiling identified three distinct SS subtypes resembling the known histological subtypes: SS subtype I and was characterized by hyperproliferation, evasion of immune detection and a poor prognosis. SS subtype II and was dominated by a vascular‐stromal component and had a significantly better outcome. SS Subtype III was characterized by biphasic differentiation, increased genomic complexity and immune suppression mediated by checkpoint inhibition, and poor prognosis despite good responses to neoadjuvant therapy. Chromosomal abnormalities were an independent significant risk factor for metastasis. KRT8 was identified as a key component for epithelial differentiation in biphasic tumors, potentially controlled by OVOL1 regulation. Our findings explain the histological grounds for SS classification and indicate that a significantly larger proportion of patients have high risk tumors (corresponding to SS subtype I) than previously believed. [ABSTRACT FROM AUTHOR]

Regulatory T cells (Tregs) are instrumental in maintaining immune tolerance and preventing destructive autoimmunity, but how heterogeneous Treg populations are established remains largely unknown. Here, we show that Zfp335 deletion in Tregs failed to differentiate into effector Tregs (eTregs) and lose Treg-suppressive function and that KO mice exhibited early-onset lethal autoimmune inflammation with unrestricted activation of conventional T cells. Single-cell RNASeq analyses revealed that Zfp335-deficient Tregs lacked a eTreg population and showed dramatic accumulation of a dysfunctional Treg subset. Mechanistically, Zfp335-deficient Tregs displayed reduced oxidative phosphorylation and dysfunctional mitochondrial activity. Further studies revealed that Zfp335 controlled eTreg differentiation by regulating fatty acid oxidation (FAO) through direct targeting of the FAO enzyme Hadha. Importantly, we demonstrate a positive correlation between ZNF335 and HADHA expression in human eTregs. Our findings reveal that Zfp335 controls FAO-driven eTreg differentiation to establish immune tolerance., Introduction Regulatory T cells (Tregs) expressing forkhead box P3 (Foxp3) play a key role in the establishment and maintenance of peripheral immune tolerance through the prevention and suppression of autoimmunity [...]

The migration is the key step for thymic T cells to enter circulation and then lymph nodes (LNs), essential for future immune surveillance. Although promoter‐based transcriptional regulation through Foxo1, Klf2, Ccr7, and Sell regulates T‐cell migration, it remains largely unexplored whether and how enhancers are involved in this process. Here we found that the conditional deletion of Med1, a component of the mediator complex and a mediator between enhancers and RNA polymerase II, caused a reduction of both CD4+ and CD8+ T cells in LNs, as well as a decrease of CD8+ T cells in the spleen. Importantly, Med1 deletion hindered the migration of thymic αβT cells into the circulation and then into LNs, accompanied by the downregulation of KLF2, CCR7, and CD62L. Mechanistically, Med1 promotes Klf2 transcription by facilitating Foxo1 binding to the Klf2 enhancer. Furthermore, forced expression of Klf2 rescued Ccr7 and Sell expression, as well as αβT‐cell migration into LNs. Collectively, our study unveils a crucial role for Med1 in regulating the enhancer‐based Foxo1‐Klf2 transcriptional program and the migration of αβT cells into LNs, providing valuable insights into the molecular mechanisms underlying T‐cell migration. [ABSTRACT FROM AUTHOR]

Curcumin (CUR) is a natural compound extracted from turmeric (Curcuma longa), which has been reported to be a promising anti-cancer drug in various cancers. However, poor water solubility and low bioavailability posed a challenge for clinical application of curcumin. In this work, four CUR prodrugs, namely PEG4000-SS-CUR, PEG1500-SS-CUR, PEG4000-SeSe-CUR and PEG1500-SeSe-CUR were synthesized. These four CUR prodrugs have high CUR loading content and can self-assemble into spherical nanoparticles (NPs) with particle size of 90–190 nm in aqueous solution. The four CUR prodrug NPs exhibit good colloidal stability in PBS buffer and promoted drug release in response to GSH. Due to the enhanced water solubility, the four CUR prodrug NPs all exhibit reduced cellular uptake amount as compared to CUR in in vitro cellular uptake study. The four CUR prodrug NPs exhibit similar cytotoxicity against 22Rv1 cells as compared to free CUR while PEG4000-SeSe-CUR NPs exhibit the highest cytotoxicity and induce the highest cell apoptosis ratio against 4T1 cells in in vitro antitumor effect study. PEG4000-SeSe-CUR NPs developed in this work were proven to be an effective nanoformulation of CUR against 4T1 cells. [ABSTRACT FROM AUTHOR]

Activation of cuproptosis pathway has been reported to hold great potential in the application of tumor treatment. But the efficacy of cuproptosis seriously limited by the insufficient accumulation in the tumor sites. Therefore, herein based on the strong stabilization effects of the metalloid element selenium (Se) on copper (Cu), a photothermic Cu2‐xSe nanoparticle encapsulated with bioresponsive dimethyl maleic anhydride (DMMA@Cu2‐xSe) as a copper‐carrier to improve the copper accumulation in tumor is constructed, thus achieving cuproptosis‐driven enhancement of thermotherapy. This nanosystem exhibits the enhancement of tumor cellular uptake by a weak acid‐triggered charge‐switching ability. Next step, the exposed Cu2‐xSe is oxidized and releases divalent copper by high‐level oxide. Then, the abundant copper induces more dihydrolipoamide S‐acetyltransferase oligomerization to down‐regulate FDX1 and tricarboxylic acid cycle‐related proteins, which leads to inhibiting aerobic respiration. Cuproptosis‐induced mitochondrial damage further improves thermotherapy by up‐regulating reactive oxygen species (ROS). In addition, the generated ROS also promotes copper release to strengthen cuproptosis, and eventually improves tumor thermotherapy in turn. In general, DMMA@Cu2‐xSe with sequentially triggered copper‐release, efficient cuproptosis, and appropriate photothermal is a self‐enhanced nanoplatform for cuproptosis‐driven enhancement of thermotherapy. [ABSTRACT FROM AUTHOR]