Cell Reports Medicine最新文献

Chimeric antigen receptor (CAR) cell therapy transforms hematologic cancer treatment but remains limited in solid tumors due to stromal barriers and an immunosuppressive tumor microenvironment that restricts immune cell infiltration. To address these barriers, we develop a cell-free therapeutic platform based on CAR-engineered induced pluripotent stem cell (iPSC)-derived natural killer (NK) extracellular vesicles (CAR-iNEVs), which retain tumor-targeting capability without reliance on live-cell delivery. CAR-iNEV demonstrates potent antitumor activity and excellent tolerability across multiple xenograft and patient-derived models. Mechanistically, CAR-iNEV directly eliminates tumor cells and remodels the tumor microenvironment by promoting pro-inflammatory macrophage polarization, thereby enhancing host innate antitumor immunity. CAR-iNEV also functions cooperatively with immune checkpoint blockade, and combined treatment with CAR-iNEV and CD47 inhibition increases tumor clearance and induces long-term immunological memory in surviving mice. These findings support the therapeutic potential of CAR-iNEV for solid tumors through coordinated tumor targeting and immune microenvironment modulation.

Watershed infarction (WI) is heterogeneous. This study aims to explore the effect of clopidogrel-aspirin in patients with WI and which WI patterns could gain more benefits. Patients are classified into cortical WI (CWI) (n = 484), internal WI (IWI) (n = 372), CWI+IWI (n = 410), and non-WI (n = 4,033) according to diffusion-weighted magnetic resonance imaging. The results show that patients with WI treated with clopidogrel-aspirin have a lower risk of stroke recurrence compared to aspirin at 90 days (hazard ratio [HR], 0.67; 95% confidence interval [CI], 0.49-0.93). Specifically, patients receiving clopidogrel-aspirin show a lower rate of recurrent stroke than those receiving aspirin in IWI (HR, 0.54; 95% CI, 0.30-0.97), and with a similar trend in CWI+IWI, but not significant in CWI (p for interaction = 0.41). Clopidogrel-aspirin does not increase moderate-to-severe bleeding across WI patterns. This study reveals that the effect of clopidogrel-aspirin appears consistent across WI subgroups, but it might be more effective in patients with IWI. This study is registered at Clinicaltrials.gov (NCT03635749).

Access to safe drinking water is a fundamental determinant of global health. In this umbrella review, we synthesized evidence from 25 systematic reviews and meta-analyses, covering 158 outcomes, to assess health risks and intervention effectiveness (PROSPERO: CRD420251001778). Employing a rigorous methodological framework including A Measurement Tool to Assess Systematic Reviews 2 (AMSTAR 2); Evidence Classification; the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE); and simplified evidence-to-decision criteria, we identified significant associations between unsafe drinking water and various health conditions, including infectious diseases, cancers, cardiovascular diseases, and adverse maternal-child health outcomes. Importantly, while the certainty of evidence for precise risk attribution remains limited, evidence supporting effective interventions is robust. Point-of-use (POU) filtration reduces childhood diarrhea by 52% (relative risk [RR] = 0.48; moderate-certainty evidence), and defluoridation effectively prevents fluorosis. Overall, these findings support a shift in policy focus: despite uncertainties in exact risk quantification, public health strategies should prioritize immediate implementation of proven interventions to safeguard vulnerable populations.

Peripheral nerve injury causes muscle atrophy due to slow axonal regeneration, highlighting an unmet therapeutic need. Although neuromuscular interactions are classically viewed as unidirectionally nerve dominated, we show that acutely denervated muscle (adMu) regulates nerve regeneration via a retrograde signaling pathway. adMu initiates a trans-tissue regulatory mechanism through extracellular vesicles (EVs^adMu) that orchestrate neural energy homeostasis to accelerate regeneration. Functional profiling identifies IDH2 and CS as key metabolic enzymes within EVs^adMu. Neurons treated with EVs^adMu exhibit a 1.39-fold increase in NADPH/NADP⁺ ratio via IDH2, along with a 1.18- and 1.27-fold increase in NADH/NAD⁺ and FADH₂/FAD ratios via CS, fueling the tricarboxylic acid (TCA) cycle to enhance mitochondrial bioenergetics. This restores redox balance and energy supply, driving axonal regeneration. In sciatic nerve injury models, EV^adMu-microneedle conduits significantly promote energy metabolism and functional recovery. Together, our findings position adMu as a metabolic signaling center enabling retrograde regulation for nerve regeneration, offering potential for clinical translation.

Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) represents a therapeutically challenging, high-risk leukemia subtype whose comprehensive proteomic characterization remains limited. Our integrated 4D label-free proteomic analysis delineates a distinct molecular signature featuring profound oxidative phosphorylation (OxPhos) deficiency, characterized by compromised mitochondrial ATP synthesis and significant reductions in electron transport chain complexes I and IV. Single-cell RNA sequencing validation establishes that stem-like ETP-ALL populations exhibit substantially diminished ETC activity relative to T-lineage-differentiated counterparts. Pharmacological intervention using dichloroacetate to restore OxPhos functionality effectively suppresses leukemic proliferation and xenograft engraftment through ROS-mediated endoplasmic reticulum stress activation. Furthermore, we identify CD109 as an attractive immunophenotypic marker that not only distinguishes ETP-ALL from other hematologic malignancies but also defines a subset with enhanced ETC suppression and heightened metabolic vulnerability to dichloroacetate. These findings elucidate the mechanistic basis of mitochondrial dysregulation in ETP-ALL pathogenesis and nominate CD109 as a promising biomarker for targeted therapeutic strategies.

Evolution of SARS-CoV-2 in long-term persistent infections is hypothesized to be a major source of variants of concern (VOCs). However, linking intra-host variants into haplotypes that reflect viral subpopulations is limited by commonly used genomic sequencing techniques. We develop sequencing and analysis methods for identifying full-length spike haplotypes and analyze their diversification during persistent infections in individuals with inherited or acquired immunodeficiencies. This reveals accelerated evolutionary rates, with mutations frequently emerging at VOC-associated sites that confer escape from neutralizing antibodies, often undergoing strong positive selection. In a single infection lasting over 500 days from the first wave of the pandemic, we detail the evolution of spike as it acquires mechanisms to evade both autologous and heterologous neutralizing antibodies, redolent of Omicron variants. This evidence reinforces the argument for persistent infections being the source of immune-evasive variants, underscoring their impact on the evolutionary trajectory of SARS-CoV-2.

Chimeric antigen receptor (CAR)-T cell therapy targeting antigens shared with normal T cells requires genetic modifications to prevent fratricide. This phase 1 trial evaluates autologous CD5-targeting CAR-T cells with CD5 gene deletion (CT125A) in seven patients with relapsed/refractory CD5⁺ hematologic malignancies. The overall response rate is 85.7%, including four complete responses. All patients experience cytokine release syndrome (six grade 1-2, one grade 3), and two patients develop immune effector cell-associated neurotoxicity syndrome. The most common grade ≥3 adverse events are cytopenia and infection, with unique observations of rash and autoimmune-related events. Post-infusion immunophenotyping shows persistent depletion of CD5⁺ T cells and CD19⁺ B cells, with reduced CD4/CD8 ratios. The human CD5 knockin murine model reveals skin lesions without significant vital organ involvement. These findings demonstrate CT125A's therapeutic potential in CD5⁺ malignancies while highlighting the need for safety optimization. The trial has been registered at ClinicalTrials.gov (NCT04767308).

The emergence of highly pathogenic avian H5N1 influenza viruses in dairy cows and humans has increased the potential for another pandemic. To address this risk, we developed chimpanzee adenoviral (ChAd)-vectored H5 hemagglutinin-targeted vaccines and tested their immunogenicity and efficacy in rodents. Immunization with ChAd-Texas (clade 2.3.4.4b) vaccine in mice elicits neutralizing antibody responses and confers protection against viral infection and mortality upon challenge with a human H5N1 isolate (A/Michigan/90/2024, clade 2.3.4.4b). Intranasal delivery of the ChAd-Texas vaccine elicits mucosal antibody and T cell responses and confers greater protection than intramuscular immunization. In Syrian hamsters, a single intranasal dose of ChAd-Texas vaccine prevents weight loss and reduces airway infection after H5N1 A/Michigan/90/2024 or A/Texas/37/2024 challenge. Importantly, prior seasonal influenza vaccination does not impair antibody responses or protection after intranasal delivery of the ChAd-Texas vaccine. These results support the development of mucosally administered ChAd-Texas HA vaccines as an effective platform for HPAI H5N1 preparedness.

Bone is a common site for cancer metastasis, yet the mechanisms driving human spinal bone metastases (BMs) are poorly understood. Here, we obtained a single-cell RNA sequencing (scRNA-seq) atlas of 62 BMs across 13 different origins, along with paired primary tumor and normal bone marrow. Unsupervised clustering of cancer cell functional programs revealed 3 groups with distinct prognosis and tumor microenvironment. Integrative analysis with large-scale primary and metastatic pan-cancer and healthy bone marrow scRNA-seq datasets revealed SELE-positive endothelial cells, osteoblasts, and osteoclasts associated with cancer cell proliferation. We also identified BM-enriched exhausted CD8⁺ T cells with increased expression of immune checkpoint genes. In bone metastatic mouse models, a combined anti-PD-1/TIGIT immune therapy effectively suppressed tumor cell proliferation and significantly enhanced the cytotoxic activity of CD8⁺ T cells. Our results provide a systematic view of the molecular basis of BM and suggest future avenues for immunotherapy optimization for BM patients.

General anesthesia induces reversible changes in consciousness through cortical activity and connectivity alterations, yet the functional connectome dynamics underlying propofol-induced unconsciousness remains unclear. We analyze high-density 128-channel electroencephalogram (EEG) from 31 surgical patients using source localization to identify neurobiological connectome signatures of propofol anesthesia. Propofol anesthesia increases delta and theta functional connectivity and decreases alpha, beta, and gamma connectivity. A classification model and dynamic analysis of consciousness loss reveals that alpha-band connectivity between parietal, occipital, and subcortical regions is critical for sustaining consciousness, with its disruption marking a key transition to unconsciousness. EEG from 46 additional patients under mild sedation with low-dose propofol confirms that decreased parietal-related alpha connectivity serves as a stable marker of reduced consciousness, insensitive to subtle fluctuations but sensitive to the transition from consciousness to unconsciousness. These findings suggest that parietal, occipital, and subcortical alpha connectivity serves as a reliable neural correlate of propofol-induced unconsciousness.