Cell Reports Medicine最新文献

The rapidly increasing global incidence of youth-onset diabetes is a critical public health concern. Earlier type 2 diabetes (T2D) onset in children and young people is characterized by faster progression and higher risk for complications. An area of expanding research is understanding how obesogenic environments modify the composition and function of the gut microbiota and, in turn, modulate host immune response as well as metabolism. The association between obesity and altered gut microbiota is complicated by hormonal changes during puberty and chronic inflammation that potentiates insulin resistance in multiple responsive tissues. This review examines the risk factors and mechanisms underlying T2D pathogenesis in children and young people and current evidence connecting gut microbiota to stages of disease progression and treatment opportunities. The potential for early intervention through modifications of the gut microbiota opens avenues to alleviate metabolic complications in critical developmental period and blunt the risk for early T2D onset.

We previously showed that enrichment of the Bacteroides genus is associated with improved anti-PD-1-mediated tumor therapy. Here, we isolate 183 Bacteroides isolates from the feces of humanized anti-PD-1 responder mice. Supernatants from 6 of 183 isolates stimulate IFNγ production from primary CD8⁺ T cells. These six isolates (6-consort) enhance anti-PD-1-induced anti-tumor efficacy in syngeneic and orthotopic lung cancer models compared to non-responder feces-colonized mice, an effect dependent on the production of IFNγ. Bioassay-guided fractionation and comparative metabolomics lead to the discovery of an active N-acyl amide (cis-Bac429) produced by Bacteroides. cis-Bac429 stimulates IFNγ production by CD8⁺ T cells but not synthetic saturated Bac429 (sat-Bac429), indicating structural specificity. Intratumorally administered cis-Bac429, but not sat-Bac429, significantly decreases subcutaneous lung and colon tumor growth in combination with anti-PD-1 therapy and drives IFNγ+ CD8⁺ T cell tumor infiltration. These findings pave the way for development of Bacteroides-type N-acyl-amides as adjuvant treatments for anti-PD-1-refractory NSCLC.

During deep co-evolution of viruses and host cells, viruses have selected specific host cellular proteins redirected from physiological functions to viral needs, thereby disturbing cellular proteostasis and increasing the risk of triggering protein misfolding diseases (PMDs). Identifying virus-specific, repurposed host proteins also allows the study of fundamental cellular events in "sporadic" PMDs, independent of the virus. Here, we identify a small molecule with very strong activity against neurotropic herpes simplex virus 1 (HSV-1), modulating an allosteric site of macrophage migration inhibitory factor (MIF). The compound efficiently reduces both HSV-1-mediated and non-mediated tau phosphorylation or aggregation in vitro and in vivo. The lead compound, as well as conformation-sensitive antibodies, specifically interacts with an oxidized conformer of MIF (oxMIF) enriched in postmortem brain homogenates of patients with Alzheimer's disease (AD). OxMIF thus participates in a host-viral interface connecting HSV-1 infection, and possibly other external stressors, with tau cellular pathology characteristic for PMDs, including AD.

Early risk recognition for organ dysfunction and death by Clostridioides difficile infection (CDI) is an unmet need. A prediction score is developed in the BEYOND study (ClinicalTrials.gov; NCT02573571, NCT04725123, and NCT05304715). At the first stage, using 153 patients and 150 comparators, the BEYOND score was developed integrating hemoglobin; blood urea; blood interleukin-8; carriage of G alleles of rs2091172; and presence of Terrisporobacter glycolicus, Enterococcus avium, and Anaerovorax odorimutans in the stool. The score had 84.6% sensitivity and 95.8% specificity for unfavorable outcomes. At the second stage, a double-blind randomized controlled trial was performed, and 44 patients at high-risk by BEYOND score were treated with standard-of-care plus Bezlotoxumab or placebo. The primary endpoint was the incidence of organ dysfunction, CDI relapse, and/or death. This endpoint was met in 72.7% of patients in the placebo arm and 31.8% in the Bezlotoxumab arm (p = 0.015). Results suggest that BEYOND score can detect early risk in patients with CDI.

The dual challenges of limited therapeutic options due to de novo or acquired resistance and psychological distress in patients with melanoma necessitate innovative treatment strategies. Here, we identify paroxetine hydrochloride (PH), a Food and Drug Administration (FDA)-approved antidepressant, as an alternative therapeutic for BRAF^V600E-mutated melanoma, including BRAFi/MEKi-resistant cases. Furthermore, our findings reveal that PH acts as an unrecognized inducer of pyroptosis. By triggering pyroptosis, PH remodels the tumor-permissive microenvironment in recurrent melanoma to potentiate anti-PD-1 therapy while maintaining a favorable safety profile. Mechanistically, PH impedes 5-hydroxytryptamine (5-HT) reuptake, leading to epigenetic reprogramming by reducing histone serotonylation (H3Q5ser) at the promoters of DNA repair genes. Impaired DNA damage repair pathways in turn trigger genome instability, proteostasis imbalance, and subsequent endoplasmic reticulum stress, ultimately inducing pyroptosis. Our findings uncover the underlying mechanism by which 5-HT drives melanoma progression and highlight PH as a promising candidate with multiple clinical potentials for treating melanoma.

Among acute myeloid leukemia (AML) patients, a subgroup remains notoriously refractory to current treatment options, with underlying mechanisms poorly understood. Here, using a multi-omics approach, we reveal that this resistant patient subgroup is characterized by high expression of the oncogenic TP73 isoform ΔNp73, exhibiting similarly poor outcomes as TP53-mutant AML. ΔNp73, which lacks a transcriptional activation domain but retains chromatin-binding properties, competes with TP53 for specific gene targets, thereby downregulating TP53 signaling. We demonstrate that the transcription factor CEBPA controls ΔNp73 expression in AML cells by binding to an intragenic enhancer region. Genetic or pharmacological inhibition of the transcriptional activity of CEBPA with guanfacine reduces ΔNp73 levels and restores drug sensitivity involving ferroptosis-mediated cell death, acting synergistically with venetoclax. Our study sheds light on a previously undercharacterized poor-risk subgroup of AML, which may support patient stratification and inform treatment considerations.

Hepatocellular carcinoma (HCC) features a tumor immunosuppressive microenvironment (TIME) and limited response to immune checkpoint inhibitors (ICIs). To address this, we develop ultrasound-responsive nanoparticles by encapsulating PD-L1-targeting small interfering RNA (siRNA) and sonodynamic metal-organic frameworks (MOFs) into bacterial membrane vesicles (BMVs) derived from Akkermansia muciniphila. The siRNA-MOF@BMV (SMB) demonstrates HCC-specific accumulation via N-acetylgalactosamine (GalNAc) and induces pyroptosis through NLRP3/Caspase-1/GSDMD pathway activation under ultrasound, releasing tumor antigens. Simultaneously, SMB further induces trained immunity in tumor-associated macrophages (TAMs), promoting CXCL9⁺ phenotypes that enhance antigen presentation and chemotaxis capacity. This increases cytotoxic CD8⁺ T cell infiltration and reduces exhausted T cells, reshaping the TIME. Furthermore, SMB exhibits superior tumor suppression compared to clinical ICIs through systematic evaluations in orthotopic HCC mouse models, primary HCC models, patient-derived xenograft (PDX), and organoid models. SMB presents a multifunctional immunotherapeutic strategy integrating targeted pyroptosis induction, innate immune training, and ICI delivery, representing a potent immunotherapeutic agent for HCC.

In the United States, an estimated 14 million colonoscopies are performed yearly, each requiring patients to undergo bowel preparation, a laxative cleansing of the intestine's luminal contents. Despite its widespread use, the effects of bowel preparation on gut physiology and susceptibility to pathogens remain poorly understood, particularly in individuals with compromised gut health. Using mouse and in vitro models, we find that bowel preparation with the laxative polyethylene glycol rapidly disrupts the gut, transiently increasing susceptibility to infection by Salmonella Typhimurium, including a non-motile mutant, and by gut pathobionts derived from ulcerative colitis microbiota. Bowel preparation also facilitates bacterial translocation to extraintestinal sites (mesenteric lymph nodes, liver, and spleen) and exacerbates inflammation in a chemically induced colitis model. Although these findings are preclinical, they suggest that bowel preparation may have underappreciated risks in vulnerable populations and warrant further clinical investigation.

This study explores the role of efferocytosis in esophageal squamous cell carcinoma (ESCC) using single-cell RNA sequencing and in vitro/in vivo assays. Analyzing 27 samples from 9 patients with ESCC, we identify diverse cell types and significant heterogeneity in the tumor microenvironment, with a focus on efferocytosis. Our findings highlight that macrophages engulf apoptotic tumor cells, thereby impairing immune responses and promoting tumor progression. Notably, TP63 and RAC2 emerge as key regulators of this process, influencing efferocytosis and immune modulation. Functional assays demonstrate that disrupting these pathways alters macrophage efferocytosis and impacts tumor growth in vivo. These results suggest that targeting efferocytosis pathways offers potential therapeutic strategies for ESCC, enhancing antitumor immunity and improving patient outcomes. The study underscores the complex interactions between tumor cells and the immune system, with efferocytosis representing a promising therapeutic target.

DF6215 is a rationally engineered interleukin-2 (IL-2) Fc-fusion protein developed to overcome efficacy and safety limitations of traditional IL-2 cancer immunotherapy. Unlike non-alpha (non-α) IL-2 variants that eliminate CD25 binding and underperform clinically, DF6215 retains moderate IL-2 receptor α (IL-2Rα) affinity while enhancing IL-2Rβγ signaling and extending the half-life via an engineered immunoglobulin (Ig)G1 Fc domain. This design preferentially expands cytotoxic CD8⁺ T cells and natural killer cells over regulatory T cells, resulting in favorable effector-to-regulatory cell ratios, enhanced immune activation, and robust tumor regression in mouse models. In poorly immunogenic tumors, DF6215 synergized with PD-1 blockade to achieve durable responses without added toxicity. Cynomolgus monkey studies confirm DF6215's pharmacodynamics and favorable safety profile, with no signs of vascular leak syndrome or cytokine release syndrome. These findings position DF6215 as a differentiated IL-2 capable of modulating the tumor microenvironment and achieving potent anti-tumor immunity with improved tolerability, supporting its advancement into clinical trials for solid tumors.