Cell Reports Medicine最新文献

Hemoglobinopathies, including beta-thalassemia (Bthal) and sickle cell disease (SCD), are among the most prevalent inherited blood disorders. Genetic mutations affecting hemoglobin synthesis result in severe anemia and multi-organ complications. The development of gene therapy (GT) aimed at correcting or modifying the hematopoietic system, although initially impaired by several limitations, has accomplished the marketing authorization of two hematopoietic stem cell (HSC) medicinal products, engineered by lentiviral vector gene addition and by CRISPR-Cas9 gene editing. Nonetheless, the success of these approaches stimulates a critical revision of our knowledge of HSC biology and bone marrow (BM) microenvironment in these diseases. Here, we review the clinical application of GT by gene addition and gene editing, and the novel findings about HSC and BM niche features and function in hemoglobinopathies. The identification of defective networks in HSC-niche is examined with the perspective of developing combined strategies to ameliorate the BM microenvironment to better support the genetically corrected cells.

Alterations in fibroblast growth factor receptor 2 (FGFR2) represent potential therapeutic targets in intrahepatic cholangiocarcinoma (ICC), yet they occur in only about 10% of patients. In this study, patients with advanced ICC are tested for FGFR2 alterations via pre-enrollment biopsy; those with alterations are excluded. Eligible patients receive locoregional gemcitabine combined with camrelizumab and surufatinib until disease progression or intolerable adverse events (AEs). Between July 2022 and June 2024, 23 eligible patients are enrolled. Twelve patients achieve partial response, resulting in an objective response rate of 52.2%. The median progression-free survival is 11.3 months, and the median overall survival is 20.3 months. Eighteen patients experience at least one AE, including one grade 3 event. Exploratory analysis indicates that responders show significantly higher tumor PD-L1 expression than non-responders do, with median tumor proportion scores of 8% and 2%, respectively. The study is registered at ClinicalTrials.gov (NCT05236699).

We present Meta-EyeFM, an integrated language-vision foundation model designed for conversational diagnostics and triaging in primary eye care. By combining a large language model (LLM) with eight task-specific vision foundation models (VFMs), Meta-EyeFM dynamically routes user queries and fundus photographs to the most appropriate VFMs (accuracy 96.8%). It demonstrates high performance in detecting ocular diseases (area under the receiver operating curve [AUC] ≥91.2%), differentiating disease severity (AUC ≥82%), identifying ocular signs (AUC ≥77.9%), and predicting systemic conditions like diabetes (AUC ≥79.8%). Meta-EyeFM is 11%-43% more accurate than Gemini-1.5-flash and GPT-4o LLM and generally outperforms junior ophthalmologist and optometrist graders in detecting different eye diseases. Its conversational interface and robust generalizability support its role as a diagnostic decision support tool in community settings. Through self-supervised learning and a user-friendly platform, Meta-EyeFM addresses the scarcity of skilled eye care professionals, offering scalable, explainable AI for enhancing vision screening and disease triage globally.

Mpox is regarded as the most important orthopoxvirus infection since the eradication of smallpox, yet the determinants of protective antibody responses remain poorly defined. Here, we investigate factors shaping humoral protection against MPXV and observe a moderate correlation between orthopoxvirus antibody levels and age among vaccinia virus (VACV)-vaccinated individuals. No correlation is found between orthopoxvirus-binding antibodies and gender. Pre-existing humoral immunity does not impair the induction of MPXV-specific antibody responses in mpox cases. Despite a high seropositivity rate for neutralizing antibodies in both mpox cases and vaccinated individuals, the overall titers remain modest. Quantitative analyses identify MPXV antigens A29, E8, and M1 on intracellular mature virion (IMV), together with A35 and B6 on extracellular enveloped virion (EEV), as the principal targets of neutralizing antibodies elicited during both MPXV infection and vaccination. Passive transfer of plasma from mpox patients and convalescents significantly reduces viral replication in vivo. These findings provide critical insights into the correlates of protection against MPXV.

Adult neurogenesis plays a crucial role in maintaining brain homeostasis and can respond to neurogenic injuries. However, the adult mammalian spinal cord has extremely limited intrinsic neurogenic ability. Here, we show that in vivo astrocyte-to-neuron conversion can regenerate functional neurons after spinal cord injury (SCI) through CRISPRa-mediated activation of endogenous transcription factors Ngn2 and Isl1. Lineage tracing confirms that the origin of these induced neurons is reactive astrocytes, rather than endogenous neurons. Furthermore, these induced neurons express specific markers of motor neurons and glutamatergic neurons and form synaptic connections with ascending and descending spinal pathways. Importantly, astrocyte-to-neuron conversion promotes propriospinal axon regeneration, improves the neuromuscular junction (NMJ) morphology and function of muscle, and finally promotes motor functional recovery after SCI. In summary, our results would contribute to resolving the controversy surrounding lineage reprogramming and demonstrate that in vivo cell conversion may be a potential therapeutic strategy for treating SCI.

After the primary response, circulating memory CD4⁺T effector and T regulatory (Treg) cells regulate recall responses, typically impaired in allergy. We discovered distinct metabolomes of these cells in humans, differentially enriched in phenylalanine-related metabolites. Energy metabolism assessment in in vitro and ex vivo single-cell analyses revealed that increased intracellular L-phenylalanine boosts glycolysis while limiting oxidative phosphorylation (OXPHOS) in CD4⁺T, memory CD4⁺T, and Th2 cells, but not in Th1, Th17, or Treg cells. L-phenylalanine also restrains proliferation of memory CD4⁺T, Th2, and Th17 cells in an IL4I1-dependent manner and limits Th2 differentiation via inhibition of STAT6 and mechanistic target of rapamycin (mTOR) signaling. RNA sequencing, metabolomics, flow cytometry, and proteomics, validated both in vitro and across patient cohorts, revealed impaired LAT1-dependent transport of L-phenylalanine into Th2 cells in allergy, with increased intracellular processing accompanied by expansion of pathogenic Th2 cells. Thus, our study identifies L-phenylalanine as a checkpoint in Th2 cell development, energy metabolism, and function.

The clinical diagnosis of epilepsy is predominantly based on history taking, morbidity records, and imaging during seizures. The emergence of proteomics has enhanced disease marker detection and potential drug target identification. We perform a longitudinal survival analysis of 2,920 plasma proteins and epilepsy onset, utilizing plasma proteome data from 52,372 UK Biobank participants (440 incident cases). We identify 103 proteins with significant associations with epilepsy, with neurofilament light polypeptide (NEFL) (hazard ratio [HR] [95% confidence interval (CI)]: 2.13 [1.85-2.46]) and growth differentiation factor 1 (GDF15) (1.82 [1.60-2.07]) exhibiting the strongest correlations. Enrichment and network analyses uncovered the pivotal role of the immune response and pinpointed four central hubs. Furthermore, 103 screened proteins are significantly associated with brain regions implicated in epileptogenesis and show stronger correlation with stress-related events than genetic predisposition. We investigate the predictive ability of top-ranked proteins for future epilepsy risk and their potential as drug targets. These findings are crucial for identifying early biomarkers and optimizing therapeutic strategies.

Dendritic cells (DCs) are potent antigen-presenting cells, key for inducing anti-tumoral immune responses in the tumor microenvironment (TME) and tumor-draining lymph nodes. Within the TME, immunosuppressive signals often render DCs dysfunctional, hindering their propagation of T cell-mediated cancer cell death and tumor regression. DC-based immunotherapy has been investigated for over two decades, aiming to induce anti-tumor immunity by directly delivering DCs or antigens through vaccination or by enhancing the anti-tumor functions of existing DCs within the TME. Despite some progress, clinical benefit in many patients is still limited. As our understanding of the complex interactions that occur in the TME deepens and new technologies emerge, novel DC immunotherapy strategies are continuously being developed and advanced into clinical trials. This review provides an updated summary of the latest advances in these therapies, identifying trends that correlate with successful outcomes, as well as the challenges still being faced in the field.

Renal medullary carcinoma (RMC) is a rare but highly aggressive kidney cancer that resists conventional therapies. To identify therapeutic targets, this study employs histopathologic, genomic, and transcriptomic profiling of 25 RMC samples. TROP2, EPCAM, CLDN6, and CDH6 are significantly overexpressed compared with other renal and solid tumors. Pathway analyses indicate Hippo pathway upregulation and a tumor microenvironment rich in fibroblasts and neutrophils. We subsequently explore treatment of four heavily pretreated patients, all with high TROP2 expression, using sacituzumab govitecan, a TROP2-targeted antibody-drug conjugate. Of these four patients, one patient achieves a partial response with symptom improvement, two patients maintain stable disease, and the median progression-free survival reaches 2.9 months. This study represents the most extensive molecular characterization of RMC to date, identifying TROP2 and other potential therapeutic targets. Sacituzumab govitecan demonstrates potential clinical benefit, warranting further evaluation in prospective trials to confirm its efficacy and explore additional targets identified herein.

Ferroptosis is recognized as a form of regulated cell death characterized by iron-dependent lipid peroxidation and significant immunogenic properties. However, we observe that the hypoxic tumor microenvironment (TME) of solid tumors severely limits ferroptosis induction and antitumor immune responses, while simultaneously promoting programmed death-ligand 1 (PD-L1) expression, thereby further compromising tumor immunotherapy. Herein, we exploit a fluorinated prodrug-engineered nano-remodeler to reverse the hypoxic and immunosuppressive TME for enhancing ferroptosis/immunomodulation-driven antitumor therapy. The nano-remodeler is elaborately co-assembled by the disulfide-bonded fluorinated JQ1 prodrug (a PD-L1 inhibitor) and sorafenib (Sor, a ferroptosis inducer). As expected, the ferroptosis induction efficiency and antitumor immunogenicity of Sor are significantly improved due to oxygen supply in hypoxic solid tumors, resulting in a highly synergistic ferroptosis-immunotherapy with JQ1. As a result, this nano-remodeler exerts a potent tumor inhibitory effect in multiple tumor models. This study provides insights into the nanotherapeutic paradigm of tumor hypoxia intervention in multimodal ferroptosis-immunotherapy.