Cell Reports Medicine最新文献

Triggering receptor expressed on myeloid cells 2 (TREM2), a critical sensor of cell debris, regulates macrophage efferocytosis to maintain tissue immune homeostasis. However, inflammatory mediators upregulate the sheddase ADAM17, leading to TREM2 cleavage, which impairs apoptotic cell clearance and exacerbates inflammation. We here report a synthetic cleavage-resistant TREM2 (CRT) to boost TREM2-dependent efferocytosis and alleviate inflammation associated with aberrantly accumulated apoptotic cells. CRT integrates the ligand-binding domain of TREM2 with its intracellular signaling adaptor DAP12 via a custom-engineered stalk and transmembrane segment. Our data demonstrate that CRT amplifies TREM2 signaling even in the presence of ADAM17. Customized lipid nanoparticles efficiently introduce CRT mRNA into macrophages, generating CRT-engineered macrophages (CRT-Ms) in situ. CRT-Ms effectively reduce apoptotic cell burden and alleviate inflammation in mouse models of metabolic-dysfunction-associated steatohepatitis and atherosclerosis. In sum, our findings establish that CRT strengthens TREM2-mediated macrophage efferocytosis and mitigates inflammation, with broad potential for apoptotic-cell-associated diseases.

Metabolites present in the mother traverse the placenta to supply energy, essential nutrients, and communication signals to the fetus. To gain a deeper understanding of fetal metabolism and the impacts of maternal metabolic health and medications on the fetus, we have created CordDB. Using mass spectrometry, we systematically document the metabolites and medications that enter and leave the fetus during birth, as well as the associated health records of the mother and newborn. These data reveal the metabolites consumed by the fetus, microbial metabolites (e.g., 3-indolepropionic acid), metabolites obtained from diet, and medications, as well as create a healthy newborn signature. Our study demonstrates that the mother's microbial interactions and nutrition, premature birth, and the mother's use of drugs such as bupivacaine and betamethasone are linked to variations in the metabolic profiles and health of newborns.

Patients with liver metastases (LMs) derive less benefit from immune checkpoint blockade (ICB), yet the mechanism remains poorly understood. In the liver tumor microenvironment of patients with mismatch repair-deficient (MMR-d) cancers treated with immunotherapy, we observe a reduction of Vδ1⁺ γδ T cells. Hepatic Vδ1⁺ T cells express high levels of IFNγ at baseline compared to other organs. In patients with LMs, we identify elevated systemic IL18 levels compared to metastatic patients without LMs and find that its intratumoral expression is associated with ICB success exclusively in patients with LMs. While liver γδ T cells are specifically sensitive to IL18 stimulation ex vivo, cancer cells counteract IL18-driven immunity by secretion of IL18 binding protein (IL18BP). Blockade of IL18BP enhances interferon (IFN) γ-driven immunity against organoids in vitro. Taken together, we identify the IL18/IL18BP/Vδ1⁺ axis as an important regulator of ICB response and a therapeutic vulnerability for patients with LMs of MMR-d tumors.

Anti-CD19 chimeric antigen receptor T cell (CAR-T) therapy is highly effective for B cell precursor acute lymphoblastic leukemia (BCP-ALL); however, approximately half of the patients relapse. Thus, there is an urgent need to identify factors that improve efficacy. This study enrolls 19 patients with BCP-ALL (16 children and 3 young adults) who receive tisagenlecleucel. Infusion products, peripheral blood, and bone marrow samples are obtained before and after CAR-T cell infusion. Single-cell analysis reveals that central memory CAR^pos T cells increase in long-term responders, whereas CXCR3⁺CD38^highPD-1^high effector CAR^pos T cells are enriched in relapsed patients, post-infusion. By contrast, CAR^pos T cells obtained from infusion products in long-term responders are enriched in the CD38^-CD73^-Tim-3^-HLA-DR⁺ phenotype, characterized by a decreased ability to produce adenosine, memory-like transcriptomic characteristics, and leveraging of mitochondrial metabolism and oxidative phosphorylation. Our study reveals that the CD38^-CD73^-Tim-3^-HLA-DR⁺ phenotype contributes to long-term remission in patients with BCP-ALL who receive tisagenlecleucel.

From extrachromosomal DNA to neo-peptides, reprogramming of cancer genomes leads to the emergence of cancer state-specific molecules. Here, we systematically identify and characterize a large repertoire of orphan non-coding RNAs (oncRNAs), a class of cancer-emergent small RNAs, across 32 tumor types. We show that oncRNA binary presence-absence patterns represent a digital molecular barcode that captures cancer type and subtype identities. Importantly, this barcode is partially accessible from the cell-free space as cancer cells secrete a subset of oncRNAs. Leveraging large-scale in vivo genetic screens in xenografted mice, we functionally identify driver oncRNAs in multiple tumor types. In a retrospective study across 192 breast cancer patients, we show that oncRNAs are reliably detected in blood and that changes in cell-free oncRNA burden predict both short-term and long-term clinical outcomes. Together, we establish that oncRNAs have potential roles in tumor progression and clinical utility in liquid biopsies for tumor-naive minimum residual disease monitoring.

Cell surface proteins offer significant cancer therapeutic potential attributable to their accessible membrane localization and central roles in cellular signaling, yet their promise remains largely untapped due to technical challenges inherent to profiling them. Here, we employ N-glycoproteomics to analyze 85 patient-derived xenografts (PDXs), constructing Glyco PDXplorer-an in vivo pan-cancer atlas of cancer-derived surface proteins. We develop a target discovery pipeline to prioritize proteins with favorable expression profiles for immunotherapeutic targeting and validate FAT2 as a squamous-cancer-enriched surface protein minimally detected in normal tissue. Functional studies reveal that FAT2 is essential for head and neck squamous cancer (HNSC) cell growth and adhesion through regulation of surface architecture and integrin-PI3K signaling. Chimeric antigen receptor (CAR)-T cells targeting FAT2 demonstrate anti-tumor activity. This work lays the foundation for developing FAT2-targeted therapies and represents a pivotal platform to inform therapeutic target discovery across cancers.

Over the past decade, clinical trials of therapeutic cancer vaccines have evolved substantially in scope and design, renewing interest in this immunotherapy modality. Advances in sequencing technologies and an improved understanding of the tumor microenvironment have enabled precise targeting of tumor neoantigens, accelerating the development of personalized cancer vaccines. In this review, we critically evaluate the current landscape of cancer vaccines, particularly neoantigen-based approaches, in light of recent clinical trial data. Although cancer vaccines have historically demonstrated limited efficacy as monotherapies, growing evidence suggests enhanced clinical benefit when combined with other anti-cancer treatments, including immune checkpoint inhibitors. Drawing on these findings, we summarize key lessons from past efforts and highlight persistent knowledge gaps that limit broader clinical success. Finally, we discuss emerging strategies to overcome these challenges, with the aim of improving vaccine efficacy and facilitating the integration of cancer vaccines into standard-of-care treatment for cancer patients.

In the mid-2000s, mouse studies suggested that the gut microbiome might influence energy harvest, fat storage, appetite, insulin sensitivity, and inflammation. Since then, our understanding of the gut microbiome's role in obesity has advanced significantly. Mechanistic studies identified microbial metabolites, such as short-chain fatty acids, bile acids, branched-chain amino acids, tryptophan catabolites, and imidazole propionate, as key modulators of metabolism, inflammation, and gut-brain communication. Metagenomic and multi-omics technologies now provide deeper insights into the intricate interactions between microbes, metabolites, and host factors, reshaping obesity research and reinforcing the need for phenotype stratification by recognizing microbiome-driven metabolic profiles. Integrating gut microbiome data into clinical strategies may enable targeted interventions for specific obesity subtypes, advancing prevention and personalized care. However, as new anti-obesity medications emerge, it is imperative to determine how microbiome-based therapies can complement them, considering efficacy, cost, and patient-specific variability.

Despite advances in cancer immunotherapy, clinical efficacy remains constrained by immunosuppressive tumor microenvironment (TME), including PD-L1-mediated T cell dysfunction and CXCL8-driven myeloid cell recruitment. To address this, a bispecific peptide-nanozyme conjugate (BsPNEC) is engineered. Leveraging iterative structure-guided optimization, we first develop q6w, a proteolysis-resistant D-peptide targeting CXCR1/2, and conjugate it to a PD-L1-blocking peptide to generate a bispecific peptide qGA. To augment the therapeutic efficacy, qGA is conjugated to Fe₃O₄ nanozymes with peroxidase-mimetic activity. The Fe₃O₄ nanozymes catalytically decompose H₂O₂ into reactive oxygen species (ROS), thus activating the cGAS-STING pathway to potentiate CD8⁺ T cell infiltration and activation in anti-PD-1-resistant tumor model. The BsPNEC platform integrates tumor-targeted delivery, magnetic resonance imaging (MRI) contrast capabilities, and robust inhibition of tumor growth. Our findings present a synergistic immunotherapeutic strategy that simultaneously skews immunosuppressive TME and amplifies T cell immune response.