Cell Reports Medicine最新文献

Individuals with a history of breast cancer are at increased risk of developing a new breast cancer during their lifetime. Rare but high-impact somatic mutations in normal breast tissues may contribute to malignant transformation. We analyze mutations in cancer-relevant pathways across matched samples of peripheral blood, cancer-adjacent normal breast, and breast cancer from patients diagnosed before 50 years of age who carry no germline mutations in cancer-predisposing genes. Gene- and pathway-level mutation profiles and single-base substitution (SBS) signatures are compared between tissue types in two independent cohorts (Yale, n = 24; TCGA, n = 17). Cancer-adjacent normal breast tissue contains multiple acquired somatic mutations that persist in tumors. Most variants are shared across tissue types from the same individual, indicating strong germline influence. The substantial germline contribution to alterations through common and rare polymorphisms in cancer hallmark pathways supports a model of cancer risk based on the collective impact of variants in cancer-related genes.

Hematogenous metastasis is the leading cause of cancer mortality, with dysfunction of pericytes, key components of tumor vessels, playing a central role in facilitating metastatic spread. Although anti-pericyte therapies are gaining recognition for treating metastasis, current strategies that directly eliminate tumor pericytes (TPCs) may increase vascular leakiness, which paradoxically promotes further metastasis. Here, we identify a TPC-specific transcription factor heterodimer, TCF21-TCF3, which drives metastasis by enhancing collagen hydroxylation and extracellular matrix deposition. Based on the TCF21 residues that interact with TCF3, we rationally design a peptide to disrupt their dimerization and downregulate TCF21-TCF3-dependent collagen deposition. Notably, in murine models of colorectal cancer and osteosarcoma, the TCF21-derived peptide significantly inhibits metastasis by restoring the physiological gatekeeper function of pericytes on vessels, offering a potential therapeutic strategy to target TPCs and suppress metastasis. Our findings reveal a TPC-specific transcription factor heterodimer and provide a promising pericyte-targeting strategy for preventing hematogenous metastasis.

The long-term body mass index (BMI) threshold to prevent mortality among aging individuals with type 2 diabetes mellitus (T2DM) remains unclear. We quantify BMI exposure using two metrics: the percentage of time BMI above target range (TAR) and the percentage of time BMI within target range (TTR). In a cohort of 3,708 adults aged ≥40 years with T2DM and at least 5 BMI measurements across 4 years, 1,020 deaths occurred during a median 5-year follow-up. Sustained BMI ≥27 kg/m² (TAR) is positively associated with an increased risk of mortality. Furthermore, longer sustenance of BMI within the range of 18.5-26.9 kg/m² (TTR) is associated with dose-response survival benefits for all-cause, cardiovascular, and cancer mortality, respectively (all p < 0.05). The association is further validated in the China Health and Retirement Longitudinal Study cohort. These findings support that the threshold for increased mortality risk is sustained exposure to BMI ≥27 kg/m² in middle-aged and elderly adults with T2DM.

Cancer immunotherapy is only effective in a subset of patients, highlighting the need for effective biomarkers and combination therapies. Here, we systematically identify genetic determinants of cancer cell sensitivity to anti-tumor immunity by performing whole-genome CRISPR-Cas9 knockout screens in autologous tumoroid-T cell co-cultures, isogenic cancer cell models deficient in interferon signaling, and in the context of four cytokines. We discover that loss of CHD1 and MAP3K7 (encoding TAK1) potentiates the transcriptional response to IFN-γ, thereby creating an acquired vulnerability by sensitizing cancer cells to tumor-reactive T cells. Immune checkpoint blockade is more effective in a syngeneic mouse model of melanoma deficient in Chd1 and Map3k7 and is associated with elevated intra-tumoral CD8⁺ T cell numbers and activation. CHD1 and MAP3K7 are recurrently mutated in cancer, and reduced expression in tumors correlates with response to immune checkpoint inhibitors in patients, nominating these genes as potential biomarkers of immunotherapy response.

Chimeric antigen receptor (CAR)-T therapy targeting GPC3 shows unsatisfactory clinical efficacy in hepatocellular carcinoma (HCC). Combining clinical data and the immunocompetent orthotopic HCC model, we demonstrate that TREM2⁺ tumor-associated macrophages (TAMs) are critical mediators of GPC3-CAR-T resistance. We find that Trem2 deficiency synergizes with GPC3-CAR-T to enhance tumor control by expanding endogenous tumor-specific CD8⁺ T cells (not CAR-T amplification) and reeducating TAMs to an anti-tumor CXCL9^hi/SPP1^lo phenotype via metabolic reprogramming. Mechanistically, this combination enhances oxidative metabolism while suppressing glycolysis through JAK-STAT1 triggering, AMPK activation, and PI3K-AKT-mTOR inhibition. Crucially, Trem2 deficiency up-regulates CD40 expression, enabling CD40 agonism to phenocopy Trem2-deficiency effects via AMPK activation and STAT1-driven CXCL9 production. Notably, the clinical agonist sotigalimab similarly enhances human CD8⁺ T cell migration in vitro. Our findings highlight the significance of combining GPC3-CAR-T therapy with CD40 agonist as a critical pre-requisite for eliciting reeducation of TAMs and enhancing the efficacy of CAR-T therapy in HCC.

Aging increases the risk of neurodegeneration, cognitive decline, and Alzheimer's disease (AD). We report that plasma concentrations of ubiquitin C-terminal hydrolase-L1 (UCH-L1) and neurofilament light (NfL) become exponentially higher from ages 2 to 85 in cross-sectional samples, serving as neuronal death/damage biomarkers across the lifespan. UCH-L1 concentrations rise faster in females, who exhibit increased AD risk. Glial fibrillary acidic protein (GFAP) concentrations increase exponentially after age 40, especially in females. Age-adjusted UCH-L1, NfL, and GFAP plasma concentrations are greatly elevated in mildly cognitively impaired participants. Treatment of human AD trial participants with granulocyte-macrophage colony-stimulating factor (GM-CSF/sargramostim) apparently halts neuronal cell death: UCH-L1 biomarker concentrations are reduced to those of 5-year-old healthy controls. GM-CSF treatment also reduces neuronal apoptosis and astrogliosis in a rat model of AD. An exponential increase in neurodegeneration with age, accelerated by astrogliosis/inflammation, may underlie the contribution of aging to cognitive decline and AD and can be halted by GM-CSF/sargramostim treatment.

Alzheimer's disease (AD) is traditionally considered irreversible. Here, however, we provide proof of principle for therapeutic reversibility of advanced AD. In advanced disease amyloid-driven 5xFAD mice, treatment with P7C3-A20, which restores nicotinamide adenine dinucleotide (NAD⁺) homeostasis, reverses tau phosphorylation, blood-brain barrier deterioration, oxidative stress, DNA damage, and neuroinflammation and enhances hippocampal neurogenesis and synaptic plasticity, resulting in full cognitive recovery and reduction of plasma levels of the clinical AD biomarker p-tau217. P7C3-A20 also reverses advanced disease in tau-driven PS19 mice and protects human brain microvascular endothelial cells from oxidative stress. In humans and mice, pathology severity correlates with disruption of brain NAD⁺ homeostasis, and the brains of nondemented people with Alzheimer's neuropathology exhibit gene expression patterns suggestive of preserved NAD⁺ homeostasis. Forty-six proteins aberrantly expressed in advanced 5xFAD mouse brain and normalized by P7C3-A20 show similar alterations in human AD brain, revealing targets with potential for optimizing translation to patient care.

Venetoclax (ven) combined with azacytadine is a widely used therapy for acute myeloid leukemia (AML). However, most patients develop resistance. To identify more effective combinations, we analyze 302 AML patient samples and find ven plus palbociclib (ven+palbo), a cyclin dependent kinase (CDK)4/6 inhibitor, to be highly effective. Ven+palbo shows synergistic activity in AML cell lines and patient-derived xenograft mouse models. Patient samples exhibiting a synergistic response to ven+palbo show downregulation of genes involved in protein synthesis. Genome-wide (CRISPR) screening shows that loss of translational genes uniquely confers sensitivity to ven but not to ven+palbo. AML cells exposed to ven exhibit an adaptive increase of protein synthesis that is overcome by ven+palbo through regulation of translational machinery. Additionally, ven+palbo mitigates resistance mechanisms observed with single-agent ven (BAX loss) and palbo (RB1 loss). Finally, we identify the loss of IKZF1 as a mechanism of resistance to ven+palbo and show that targeting AXL is effective in IKZF1-mutated AML.

The mechanisms for failure of neoadjuvant immune checkpoint blockade (NICB), an established therapy for patients with esophageal squamous cell carcinoma (ESCC), remain unclear. We integrated single-cell RNA data from patients with ESCC pre- and post-NICB, identifying a subset of senescent EGR1-expressing B cells that correlate with poor pathological responses. EGR1 was a key transcription factor regulating B cell senescence. EGR1⁺ B cells emerged as predictors of adverse outcomes in multiple cohorts. These senescent B cells, through senescence-associated secretory phenotype (SASP), drive chronic inflammation in the tumor microenvironment (TME), promoting the inducement of immunosuppressive TREM2⁺ tumor-associated macrophages (TAMs), thereby suppressing anti-tumor immunity and contributing to NICB failure. Furthermore, fisetin was identified as an anti-senescence drug for mitigating B cell senescence and enhancing NICB efficacy. Our findings highlight the role of senescent EGR1⁺ B cells in ESCC immunotherapy failure and suggest targeting B cell senescence as a strategy to improve NICB outcomes.

Atherosclerosis is a chronic inflammatory disease driven by immune cell interactions within plaques. Nanotherapeutics targeting immune regulation offer potential for atherosclerosis treatment. However, current nanotherapies mainly focus on modulating individual immune subsets and rarely examine cross-cell anti-atherosclerotic mechanisms. Here, we develop an inorganic nanoparticle platform (PEGylated violet phosphorus nanosheets [VPNS@P]) that efficiently accumulates in the immune microenvironment of atherosclerotic plaques, particularly in macrophages and monocytes and partly T/B cells, with minimal off-target uptake. The VPNS@P platform substantially reduces plaque areas and improves plaque stability in atherosclerotic mice without observed side effects. Importantly, we unravel the underlying mechanisms of VPNS@P in atherosclerosis treatment through single-cell RNA sequencing (scRNA-seq) and experimental verification to suppress inflammation and enhance immunity, demonstrating that it effectively modulates four key immune cell populations within plaques. Additionally, VPNS@P reshapes intercellular communication among immune cells, revealing therapeutic targets for atherosclerosis. This study reveals an immune-modulating nanotherapy for atherosclerosis, highlighting the potential in treating inflammatory diseases.