Cell Reports Medicine最新文献

Despite advances in colorectal cancer (CRC) treatment, immunotherapy shows limited efficacy due to low immunogenicity. Nonsense-mediated mRNA decay (NMD) prevents the synthesis of potentially detrimental proteins. While targeting NMD has therapeutic potential, its specific effect on CRC remains uncertain. Our research discovered significant NMD activation and upregulated SMG5 expression in CRC. Inhibition of NMD by small interfering RNA (siRNA) targeting SMG5 or NMD inhibitor NMDI14 remodeled tumor microenvironment (TME) by altering innate immune cells and enhancing CD8⁺ T cells activation. NMD inhibition also activated TBK1 through upregulation of TRAF6, which was targeted by NMD through its elongated 3'-UTR in a non-canonical manner. High SMG5 and low TRAF6 expression are associated with poor immunotherapy response. Inhibiting NMD enhanced the effectiveness of immune checkpoint blockade (ICB) therapy in CRC. By uncovering the biological relevance and translational potential of targeting NMD to reconstruct TME, this study highlights its promise as a treatment strategy for CRC.

Despite the central role of p53 suppression in cancer pathogenesis, the promise of therapeutic p53 reactivation remains unrealized, with targeted and combination chemotherapies limited by efficacy, toxicity, and delivery. To overcome these challenges, we introduce a triple-action proteolysis targeting chimera (TAPTAC) that simultaneously targets three oncogenic mechanisms to reactivate apoptosis. TAPTAC1 diverts HDM2 from degrading p53 to eliminating oncogenic targets such as BET proteins, while also blocking HDMX-mediated sequestration, thereby maximizing p53 reactivation in concert with cancer protein degradation. TAPTAC1 outperforms combination treatments and PROTACs that target HDM2 and BET proteins, but not HDMX, and is broadly effective in wild-type (WT) p53 cancers, including mouse models of osteosarcoma and leukemia. Importantly, TAPTAC1 leverages cancer dependency on HDM2 to enhance selectivity and mitigate toxicity. With WT p53 retained in 90% of pediatric and 50% of adult cancers, TAPTACs provide a therapeutic platform for addressing key limitations of prior anti-cancer strategies.

We engineer a tumor-targeted genetic plasmid vector (P_αCD3&LIGHT) to systematically modulate T cell immunity. The tumor-specific telomerase reverse transcriptase (TERT) promoter drives simultaneous expression of tumor necrosis factor superfamily member 14 (LIGHT) and membrane-anchored anti-CD3 single-chain variable fragment (αCD3), which are important immunomodulators with closely clinical relevance. Secreted LIGHT induces high endothelial venule formation and chemokine secretion to recruit circulating lymphocytes, while remodeling extracellular matrix to facilitate immune cell penetration into tumor parenchyma. αCD3 establishes artificial immunological synapses between tumor cells and T lymphocytes. This dual mechanism synergistically establishes tertiary lymphoid structures de novo even within deep tumor regions, harboring stem cell-like CD8⁺ T cells and driving sustained immunity. Concurrently, αCD3-mediated T cell redirection not only amplifies TCR signaling but also reverses exhausted T cells. The orchestrated T cell immunity significantly potentiates checkpoint inhibitor and chimeric antigen receptor (CAR)-T cell therapies in "immune-cold" tumors without obvious side effects and also remarkably enhances the outcome of human CAR-T cells, demonstrating translational potential in solid tumor immunotherapy.

Targeting the colony-stimulating factor 1 receptor (CSF1R) pathway to deplete tumor-associated macrophages (TAMs) represents a promising strategy to overcome immunotherapy resistance in colorectal cancer (CRC). However, resistance to CSF1R inhibitors limits effectiveness. We find that CSF1R inhibition, while effectively reducing TAM abundance, fails to suppress tumor growth. Through imaging mass cytometry (IMC), we further reveal that the CSF1R inhibitor PLX3397 indirectly activates cancer-associated fibroblasts (CAFs), impedes T cell infiltration, and suppresses T cell function. Mechanistically, CSF1R inhibitors unexpectedly activate the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway, which promotes connective tissue growth factor (CTGF) release and subsequent CAF activation. Critically, anti-CTGF therapy rescues CSF1R inhibitor efficacy in vivo. The addition of checkpoint immunotherapy to CSF1R inhibitor and anti-CTGF in animal models leads to complete tumor regression. This combination strategy presents a potential approach to enhance the efficacy of immune checkpoint inhibitors in CRC.

Binding and neutralizing antibodies against the spike (S) protein of SARS-CoV-2 have been associated with a reduced risk of symptomatic infection. However, precise immune protection thresholds remain unclear. We aim to define systemic and mucosal antibody correlates of protection against SARS-CoV-2 infection. Our household COVID-19 cohort (the CIDS) consists of 52 families (52 index cases and 139 exposed contacts). Immunoglobulin subtyping against S of SARS-CoV-2 and HCoV-OC43 in the serum and upper respiratory tract is quantified to assess the protection provided by virus-specific pre-existing immunity. Logistic regression analyses indicate that multiple antibody isotypes are associated with reduced infection risk. Specifically, multivariable models show that systemic anti-SARS-CoV-2 S1 IgG and anti-OC43 S2 IgM independently correlate with protection. Besides, local mucosal anti-SARS-CoV-2 S IgG and HCoV-OC43 S IgA antibodies add protective potential. However, an integrated analysis reveals that systemic antibodies against SARS-CoV-2 remain the best predictor against virus infection.

Gene therapy medicinal products (GTMPs) are currently undergoing intense industrial expansion and technological advancement. However, one issue facing development of most GTMPs is the generation of unwanted immune responses. Immunomodulatory strategies are also often applied in conjunction with GTMP administration to suppress or enhance these responses. This review focusses on the global regulatory requirements for immunogenicity assessments and immunomodulation in relation to GTMPs. The specific aims are to (1) identify the principal international guidelines; (2) identify areas of concordance and discrepancy between guidelines; (3) propose areas where guidelines could be harmonized; and (4) predict areas, which future guidance may address. Methodologies used included surveillance of literature, international guidelines, advocacy initiatives, and compilation of previous regulatory advice received. Overall, there is a clear absence of and need for GTMP-specific guidance on immunogenicity and immunomodulation. Several specific measures and areas for future regulatory harmonization and coverage are proposed.

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.