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CD8+ T cells are an important weapon in the therapeutic armamentarium against cancer. While CD8+CD103+ T cells with a tissue-resident memory T (TRM) cell phenotype are associated with favorable prognoses,the tumor microenvironment also contains dysfunctional exhausted T (TEX) cells that exhibit a variety of TRM-like features. Here we deconvolute TRM and TEX cells across human cancers,ascribing markers and gene signatures that distinguish these populations and enable their functional distinction. Although TRM cells have superior functionality and are associated with long-term survival post-tumor resection,they are not associated with responsiveness to immune checkpoint blockade. Tumor-associated TEX and TRM cells are clonally distinct,with the latter comprising tumor-independent bystanders and tumor-specific cells segregated from cognate antigen. Intratumoral TRM cells can be forced toward an exhausted fate when chronic antigen stimulation occurs,indicating that the presence or absence of continuous antigen exposure within the microenvironment is the key distinction between tumor-associated TEX and TRM populations. These results highlight unique functions for TRM and TEX cells in tumor control,underscoring the need for distinct strategies to harness these populations for cancer therapies. Here the authors show that tissue-resident memory and exhausted T cells in tumors are distinct populations that are shaped by relative presence or absence of TCR signals,suggesting that a tailored therapeutic strategy is needed to target each subset. View Publication

Propofol is a commonly used anesthetic for sedation during surgery. This drug is reported to exhibit nonanaesthetic immunomodulatory and anti-inflammatory effects. Herein,we investigated the impact of topical propofol delivery with the aim of mitigating psoriatic inflammation. The antipsoriatic potency of propofol was evaluated in a cell-based study in which keratinocytes,macrophages,and neutrophils were used as models. A significant reduction in the proinflammatory effectors interleukin (IL)-6,IL-8,and CXC motif chemokine ligand (CXCL)1 was found in activated keratinocytes (HaCaT) treated with propofol. This reduction could enable baseline control. Immunoblotting suggested that the antioxidant enzymes nuclear factor erythroid 2-related factor (Nrf)2 and heme oxygenase (HO)-1 were involved in the protective effect of propofol on keratinocyte stimulation. The increase in Nrf2 and HO-1 was mediated by kelch-like ECH-associated protein (KEAP)1 downregulation. Propofol presented scavenging activity and decreased 2,2-diphenyl-1-picrylhydrazyl (DPPH) by 47%. The downregulation of cytokines/chemokines in activated macrophages (differentiated THP-1) and mouse neutrophils was also found after propofol treatment. Macrophage migration triggered by the conditioned medium of activated keratinocytes could be blocked with the intervention of propofol. The absorption level of propofol (3 mM) into intact pig skin was 1.2 nmol/mg. Skin deposition was increased to 3.7 nmol/mg after SC lipid removal to mimic psoriasiform skin. In silico molecular docking demonstrated the facile interaction of propofol with ceramides in the stratum corneum (SC). The treatment of imiquimod (IMQ)-sensitized mice with topical propofol suppressed erythema,acanthosis,and macrophage/neutrophil infiltration. Propofol also dramatically decreased cytokine/chemokine levels and epidermal thickness in the lesion. In summary,propofol exhibits anti-inflammatory and antioxidant properties to treat psoriasiform lesions. Topical propofol delivery is useful as an ideal route to accomplish antipsoriatic therapy and avoid systemic effects. View Publication

Hepatocellular carcinoma (HCC) is an aggressive malignancy that is often refractory to chemotherapy and immune checkpoint inhibitors. This therapeutic resistance is driven in part by the persistence of cancer stem-like cells (CSCs) and the development of an immune-cold tumor microenvironment. However,the upstream regulators that coordinate these malignant features remain poorly defined. In this study,we identified dysadherin as a novel upstream activator of YAP that promotes both CSC plasticity and immune evasion through the FAK/YAP/TEAD2 signaling axis. Using single-cell transcriptomic analysis,in vitro assays,and multiple in vivo models including a humanized immune mouse system,we showed that dysadherin enhances the expression of pluripotency genes,such as OCT4 and upregulates PD-L1. These changes support stem-like tumor behavior and contribute to T-cell exclusion,fostering an immunosuppressive niche. Notably,genetic knockdown or peptide-based pharmacologic inhibition of dysadherin effectively restored antitumor immune activation,suppressed metastasis and improved therapeutic responsiveness. Our findings reveal a mechanistic link between dysadherin-mediated cell adhesion signaling and the transcriptional regulation of both stemness and immune escape. Collectively,these findings establish the dysadherin/YAP axis as a key driver of HCC progression and resistance,and highlight it as a compelling therapeutic target that could overcome treatment failure in advanced liver cancer. View Publication

INTRODUCTION: Alzheimer's disease (AD) pathology is complex and involves mitochondrial dysfunction. There are emerging therapies targeting mitochondrial function in clinical trials for AD. This highlights the need for biomarkers that measure mitochondrial function. METHODS: We determined the utility of a novel blood‐based mitochondrial biomarker,the mitochondrial functional index (MFI),in the context of AD in a pilot study.RESULTS: In vitro and in vivo models of AD had a reduced MFI. MFI was lower in human AD subjects and APOE ????4 carriers. Receiver operating characteristic analysis showed MFI had a higher area under the curve than other plasma biomarkers. The MFI biomarker correlated with the Mini‐Mental State Examination (MMSE) and the Clinical Dementia Rating (CDR) scale. DISCUSSION: This study highlights the potential utility of MFI as a functional blood‐based mitochondrial biomarker to interrogate energy metabolism. Ongoing studies are examining the relationship of MFI with brain energy metabolism outcomes. Highlights: The MFI biomarker is reduced in cell and animal models of AD. The MFI biomarker is reduced in human AD subjects and APOE ε4 carriers. The MFI biomarker can discriminate between subjects with normal cognition and AD with better performance than other plasma biomarkers. The MFI biomarker correlates with cognitive scores. View Publication

Oligodendrocytes are the myelinating cells of the central nervous system. Regulation of the early stages of oligodendrocyte development is critical to the function of the cell. Specifically,myelin sheath formation is an energetically demanding event that requires precision,as alterations may lead to dysmyelination. Fatty acid β‐oxidation has been shown to be critical for the function of oligodendrocytes. We previously showed that myeloid cell leukemia‐1 (MCL‐1),a well‐characterized anti‐apoptotic protein,is required for the development of murine oligodendrocytes in vivo. Further,MCL‐1 regulates long‐chain fatty acid β‐oxidation in cancer cells through its interaction with Acyl‐CoA synthetase long‐chain family member 1 (ACSL1),an enzyme responsible for the conversion of free long‐chain fatty acids into fatty acyl‐CoA esters. Here,we introduce an in vitro system to isolate human stem cell‐derived oligodendrocyte progenitor cells (OPCs) and investigate the involvement of MCL‐1 during human oligodendrocyte development. Using this system,we pharmacologically inhibited MCL‐1 in OPCs to investigate its non‐apoptotic function at this developmental stage. We also used a motor neuron‐oligodendrocyte co‐culture system to examine the downstream effects of MCL‐1 at later developmental stages when oligodendrocytes begin to contact axons and generate myelin. We demonstrate that the mitochondrial network changes in human oligodendrocyte development resemble those reported in mouse tissue. Our findings point to MCL‐1 as a critical factor essential for proper oligodendrocyte morphogenesis. A unified model of oligodendrocyte differentiation from human embryonic stem cells revealed that MCL‐1 is critical for regulating the expression of oligodendrocyte‐related genes and the morphogenesis of myelinating oligodendrocytes. View Publication

Pre-clinical research on B and NK cell development relies on murine stromal cell-based systems with reduced physiological relevance and clinical applicability. A serum-free,fully humanized co-culture system utilizing human bone marrow-derived mesenchymal stromal cells (BM-MSCs) was developed to differentiate CB-CD34+ cells towards B and NK cell lineages. Differentiation dynamics were monitored via flow cytometry,with immunophenotypic analysis tracking progression from progenitors to mature cells. The system generated CD19+ IgM+ immature B cells and CD56+ CD16+ NK cells,recapitulating fetal stages of human lymphopoiesis. Serum-free media conditions ensured reproducibility and high overall yield of CD19+ B (35 ± 5.32%) and CD56+ NK (28.46 ± 7.01%) cell progenitors. Flow cytometry identified distinct population peaks,confirming temporal control over differentiation. This clinically relevant platform addresses the limitations of traditional models by providing a more physiologically accurate human microenvironment. The serum-free system supports applications in disease modeling,genotoxic compound screening,and mutational studies of hematopoiesis. By enabling scalable production of B and NK cells it aims to accelerate translational research for immunodeficiencies,cancer immunotherapy,and hematopoietic disorders. View Publication

Graft‐versus‐host disease is mediated by donor‐derived T cells reactive against the recipient's broadly expressed minor histocompatibility antigens (mHA). Regulatory T cells (Treg) have been explored as a therapeutic approach for chronic GVHD (cGVHD). The promising results from polyclonal Treg trials in this setting have led us to develop a Treg product specific for mismatched minor antigens between patient and donor (mTreg),circumventing broad immune suppression risks. HLA‐matched siblings of opposite sexes were used to obtain the sister's CD4+CD25hiCD127low Treg for co‐culture with the respective brother's dendritic cells as a source of mismatched mHA. We have established the optimal culture conditions resulting in the highest mTreg proliferation and viability. Comprehensive phenotyping during the ex vivo selection shows PD‐1,CTLA‐4,CD39 and HLA‐DR expression. Transcriptomic analysis revealed a switch in metabolic process,and up‐regulation of functional Treg genes. Furthermore,mTreg possess specific and potent suppressive activity,in which there is a dependency on cell‐to‐cell contact and a role for HLA class II expression on mTreg. This protocol would allow the generation of Treg specific to an array of mHA from the recipient's healthy tissues,likely providing a directed and strong suppression of cGVHD. We optimised a protocol for mHA‐specific Treg (mTreg) selection in an HLA‐matched context while defining its phenotype,transcriptional state and function. mTreg were highly activated and exerted specific,HLA class II‐,contact‐dependent suppression. This protocol can be explored as a highly personalised antigen‐specific Treg‐based therapy in future clinical trials for cGVHD. View Publication

Lens transparency relies on proper intercellular communication. Exosomes are crucial mediators of intercellular communication and play a key role in organ homeostasis and development. However,their presence and dynamics in the lens remain unclear. Here,we report endogenous exosomes in the zebrafish lens using cryaa-driven Cd63-AcGFP labeling. Live imaging revealed dynamic exosome movement within lens cells and their potential transfer to adjacent tissues. Additionally,we found that the biogenesis of Cd63+ exosomes in the lens is regulated by the Syntenin-a pathway. And Syntenin-a knockdown delayed lens development by impairing lens cell differentiation,highlighting the potential role of lens cell–derived exosomes. Furthermore,ROR1+ lens progenitor cell-derived extracellular vesicles promoted lentoid differentiation in vitro,with proteomic analysis suggesting underlying mechanisms. Overall,our study addresses the gap in direct observation of endogenous lens exosomes,providing foundational insights into lens pathophysiology and a potential strategy for modulating the lens microenvironment. Visualization of endogenous exosomes in the zebrafish lens reveals their dynamic roles in intercellular communication and development,with Syntenin-a–regulated exosome biogenesis influencing lens cell differentiation. View Publication

MYC-driven medulloblastoma (MB) is a highly aggressive brain tumor with poor prognosis and limited treatment options. Through CRISPR-Cas9 screening,we identify the Mediator-associated kinase CDK8 as a critical regulator of MYC-driven MB. Both genetic loss and pharmacological inhibition of CDK8 impair MB tumor growth. Moreover,we find that CDK8 cooperates with MYC to sustain the MYC-mediated translational program,as CDK8 depletion induces pronounced transcriptional changes in translation-associated gene sets,reduces ribosome biogenesis,and impairs protein synthesis. Mechanistically,CDK8 regulates the occupancy of RNA polymerase II at specific chromatin loci,facilitating epigenetic alterations that promote the transcription of ribosomal genes. Furthermore,combined inhibition of CDK8 and mTOR synergistically enhances therapeutic efficacy in vivo,leading to more pronounced tumor growth suppression. Overall,our findings establish a functional link between CDK8-mediated transcriptional regulation and mRNA translation,suggesting a promising therapeutic approach targeting protein synthesis for MYC-driven MB. MYC-driven medulloblastoma is an aggressive pediatric tumor with limited treatment options. Here,the authors show that CDK8 regulates ribosome biogenesis and that combined inhibition of CDK8 and mTOR demonstrates therapeutic efficacy in mouse models of this cancer. View Publication

Background: Chronic myocarditis (CMYO) progresses to fibrosis and heart failure,yet no therapies effectively target fibrosis. Fibroblast activation protein (FAP) marks pathogenic myofibroblasts,but its therapeutic potential remains unexplored in inflammatory settings.Methods: Using bulk/scRNA-seq of human myocarditis samples,we identified FAP as a fibrosis-specific marker. We engineered FAP-targeted CAR-T (FAP.CAR-T) cells and tested their efficacy in autoimmune (EAM) and viral (CVB3) myocarditis models. Human cardiac organoids (hCOs) treated with IL-17A modeled inflammatory fibrosis.Results: FAP expression correlated with fibrosis severity in patients (r = 0.96,P = 0.0028). In EAM and CVB3 models,FAP.CAR-T cells reduced fibrosis by 65% and 55%,respectively (P < 0.001),restored ejection fraction to higher than 65%. hCOs treated with FAP.CAR-T cells showed 55% less fibrosis (P < 0.05). No toxicity was observed in healthy mice.Conclusions: FAP.CAR-T cells eliminate fibrosis-driving myofibroblasts,reversing cardiac dysfunction in chronic myocarditis. This strategy,validated in human organoids,offers translatable immunotherapy for fibrosis-driven heart disease. View Publication

Osteosarcoma (OSA) is the most common primary bone tumor in children and adolescents,yet outcomes have remained largely unchanged for over 40 years. While chimeric antigen receptor (CAR) T cell therapy has shown success in blood cancers,it faces major limitations in solid tumors due to immune evasion,antigen loss,and immunosuppressive tumor microenvironments. Natural killer (NK) cells offer several advantages over T cells,including multiple killing mechanisms and lower risks of graft-versus-host disease,neurotoxicity,and cytokine release syndrome,making them promising candidates for off-the-shelf cell therapies. However,unmodified NK cells have shown limited efficacy in clinical settings due to poor engraftment,persistence,and tumor-mediated suppression. To overcome these barriers,we developed a cost-effective method to engineer CAR NK cells targeting CD70,a tumor antigen overexpressed in relapsed and metastatic OSA. We further enhanced these cells by incorporating soluble interleukin-15 (IL-15) and a dominant-negative TGF-β receptor,creating “armored” CAR NK cells. These engineered cells resist transforming growth factor β (TGF-β) suppression,secrete IL-15,and demonstrate improved cytotoxicity,persistence,and tumor homing in both in vitro and in vivo models. Our findings support CD70 CAR NK cells as a promising immunotherapeutic strategy for relapsed and metastatic OSA. Graphical abstract Engineered “armored” CAR NK cells targeting CD70 overcome immune suppression in osteosarcoma,enhancing persistence,tumor homing,and cytotoxicity. This study presents a promising off-the-shelf immunotherapy approach for relapsed and metastatic OSA,offering a potential advance where current treatments have stagnated for decades. View Publication