Molecular biomedicine最新文献

Tumor-associated macrophages (TAMs) are central constituents of the tumor microenvironment (TME), recruited from circulating monocytes through chemotactic signals, and they execute complex, multifaceted functions throughout tumor progression. Functionally heterogeneous, TAMs are broadly classified into distinct subtypes that display a dynamic duality, capable of shifting between tumor-suppressive and tumor-promoting states, though the pro-tumorigenic functions tend to dominate across multiple cancer types. The polarization of TAMs is modulated by diverse cytokines and signaling networks within the TME. Key pro-tumor mechanisms include activating proliferative signaling pathways, enhancing invasive and metastatic potential, establishing an immunosuppressive TME through immune cell interactions, and conferring therapy resistance. The spatial heterogeneity of TAMs further underscores the predictive relevance. Translational research increasingly focuses on TAM-targeting strategies such as inhibiting recruitment, depleting subsets, or reprogramming function. Emerging approaches, including nanomedicine-based targeting, macrophage-mediated therapies, and novel drug formulations, highlight the importance of combining conventional treatments with immune checkpoint inhibitors (ICIs). Such combinations help overcome therapeutic resistance and improve clinical outcomes. This review systematically summarizes recent advances in TAM biology and plasticity, biomarkers from single-cell and spatial analyses for distinguishing TAM subsets, and their prognostic relevance in immunotherapy. It also discusses TAM-targeting strategies and their synergistic potential with existing therapies. Together, these insights lay the foundation for next-generation cancer treatments that precisely target TAMs to overcome therapy resistance and improve patient survival.

Inflammatory bowel disease (IBD) is a chronic, relapsing disorder characterized by excessive inflammation and often associated with extraintestinal symptoms. Current treatments remain unsatisfactory. Although immune response gene 1 (Irg1) and its product itaconate show promise in alleviating experimental colitis, the underlying mechanisms are unclear. Here, we describe an endogenous, homeostatic pattern that controls both local and systemic inflammatory responses in experimental murine colitis. Our study identifies neutrophils in inflamed colon as the primary Irg1 source. Irg1 deficiency worsens disease severity, as shown by greater weight loss, higher disease activity index, shorter colon length, more severe tissue damage, and more neutrophil infiltration. Depleting neutrophils with Ly6G antibody worsened symptoms in wild-type mice but improved them in knockout mice, highlighting the key role of the Irg1/itaconate axis in neutrophil-mediated protection. Blood analysis showed that Irg1 deficiency increased inflammatory cells and worsened anemia. Bone marrow analysis revealed fewer granulocyte-monocyte progenitors (GMP) and more megakaryocyte-erythroid progenitors (MEP), suggesting a compensatory mechanism. We also found that Irg1 deficiency increased reverse migrated (rM-ed) neutrophils in blood and bone marrow. Exogenous itaconate (4-octyl itaconate, 4-OI) treatment significantly reduced colon inflammation, lowered rM-ed neutrophil levels, and restored hematopoietic homeostasis. RNA sequencing showed that 4-OI mainly acted by blocking NF-κB signaling, inhibiting endocytosis-related genes, and suppressing rM-ed neutrophils-related genes expression. In conclusion, the neutrophil-derived Irg1/itaconate axis plays a key role in mucosal repair and may help maintain hematopoietic balance by regulating rM-ed neutrophils, which suggest that exogenous itaconate derivatives like 4-OI may be effective treatments for IBD.

The management of atrial fibrillation (AF) is currently undergoing a significant paradigm shift, driven by a deepening understanding of pathophysiology and the urgent need to overcome the inherent safety and durability limitations of conventional thermal catheter ablation. This review provides a comprehensive update on the evolving AF landscape, systematically connecting complex pathogenetic mechanisms, from focal triggers to progressive fibrotic substrate remodeling, with emerging diagnostic and therapeutic innovations. We critically evaluate the expanding spectrum of novel treatment modalities, with an emphasis on pulsed-field ablation (PFA), detailing its biophysical basis of irreversible electroporation, superior myocardium-selective safety profile, and accumulating clinical evidence. Furthermore, the review integrates complementary advancements, including high-resolution electroanatomic mapping systems that refine substrate characterization, hybrid surgical-catheter strategies for refractory cases, and upstream pharmacologic interventions targeting disease progression. By synthesizing contemporary data on procedural workflows and efficacy outcomes from recent randomized trials, we address persisting challenges such as lesion durability and the management of non-pulmonary vein drivers. Finally, we identify critical knowledge gaps regarding long-term comparative effectiveness and propose a phenotype-guided management framework. This approach aims to leverage these diverse emerging technologies to optimize patient selection, thereby advancing the field toward safer, more durable, and truly personalized rhythm control for the growing population of patients with atrial fibrillation.

The pharmacological control of lipid accumulation in white adipose tissue (WAT) is a key area of focus in obesity research, yet the role of deubiquitination in adipocyte lipid storage remains underexplored. We found that spautin-1, an inhibitor of the deubiquitinases ubiquitin-specific peptidase 10 (USP10) and 13 (USP13), suppressed lipid accumulation during adipogenesis. Therefore, we investigated whether blocking deubiquitination restricts adipogenesis and acts as the underlying mechanism. Mining public datasets revealed that USP10 expression is substantially increased in the adipose tissue (AT) from individuals with obesity. Moreover, USP10 exhibited a depot-specific expression pattern, with higher levels in visceral AT than in subcutaneous AT, whereas no such difference was observed for USP13. Consistently, in high-fat diet-fed mice, USP10 was markedly upregulated in gonadal WAT, whereas USP13 was undetectable. Genetic ablation of USP10 phenocopied spautin-1 treatment by reducing the expression of the components of the peroxisome proliferator-activated receptor gamma (PPARγ)/CCAAT/enhancer-binding protein alpha (C/EBPα) axis, while USP13 knockdown induced minimal effects, thus implicating USP10 as the principal mediator. Mechanistically, USP10 directly interacted with C/EBPβ and stabilized it via deubiquitination. However, spautin-1 or USP10 knockdown enhanced C/EBPβ ubiquitination and proteolysis, thereby impairing the adipogenic commitment. The overexpression of wild-type USP10, but not its catalytically inactive mutant, rescued C/EBPβ stability, thus confirming the requirement for its enzymatic activity. The administration of spautin-1 to high-fat diet-fed mice mitigated body weight gain and reduced adipose tissue mass in vivo. Notably, spautin-1 selectively suppressed USP10 and C/EBPβ in gonadal WAT without affecting the liver, which highlights the tissue-specific pharmacodynamics. Collectively, these findings define the USP10-C/EBPβ axis as a key regulator of adipogenesis and position spautin-1 as a mechanistically grounded anti-obesity candidate that warrants translational evaluation.

The prognosis of early-stage lung adenocarcinoma (LUAD) worsens significantly during the progression from adenocarcinoma in situ/minimally invasive adenocarcinoma (AIS/MIA) to invasive adenocarcinoma (IAC), emphasizing the importance of understanding the molecular mechanisms underlying this transition for effective clinical intervention. This study analyzed data from 990 eligible early-stage LUAD patients meeting the following inclusion criteria: written informed consent, absence of neoadjuvant therapy, planned surgical resection, postoperative pathological confirmation of LUAD, and an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1. Analysis of a retrospective cohort of 601 stage I LUAD patients demonstrated a significant correlation between the extent of tumor invasion and 5-year survival rates. Transcriptomic profiling revealed a progressively immunosuppressive tumor microenvironment (TME) during the AIS/MIA-to-IAC transition, characterized by dysfunctional immune cells and diminished local anti-tumor immunity. Notably, peripheral blood analysis from 389 patients showed a significant decrease in telomerase reverse transcriptase-positive (TERT +) leukocytes with tumor progression, a change detectable earlier than circulating tumor cells (CTCs). Two-year follow-up data corroborated these findings. This study elucidates key biological events in early-stage LUAD progression, revealing that the tumor remodels both local and systemic immunity to facilitate its advancement. The reduction in peripheral TERT + leukocytes emerges as a potential non-invasive biomarker for the early detection of malignant progression, supporting the rationale for immune-based interventions at earlier disease stages.

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, with its heterogeneous molecular profiles complicating prognosis prediction. Multi-omics profiling of clinical CRC specimens is particularly valuable for uncovering prognostic variables; however, such integrated studies remain scarce. Here, we applied the Multi-Omics Factor Analysis v2 framework to multi-omics data (mutations, miRNA, RNA, proteomics, phospho-proteomics) from the CPTAC-2 cohort and constructed a comprehensive CRC model. This approach identified a survival-associated latent variable, which we term the CRC Prognostic Latent Factor (CPLF). The prognostic relevance of CPLF was then rigorously validated across three independent multi-omics cohorts, encompassing 579 patients with CRC. CPLF primarily reflects extracellular matrix deposition in the tumour microenvironment, with Tensin 1 (TNS1) and Fermitin family homologue 2 (FERMT2) as the highest-weighted features. Single-cell and spatial transcriptomic analyses, supplemented by immunohistochemistry, localized CPLF-associated gene expression predominantly to myofibroblasts. Functionally, knockdown of Tensin 1 or FERMT2 in fibroblasts attenuated tumour growth in vivo. Consistently, these top-weighted components of CPLF upregulated fibronectin 1 (FN1) expression in myofibroblasts, thereby activating integrin signaling in cancer cells and enhancing tumour progression. Altogether, our findings unveil CPLF as a data-inherent multi-omics prognostic factor and establish the CPLF/FN1/integrin axis as a key pathway mediating myofibroblast-cancer cell crosstalk in CRC progression.

Tumor-infiltrating regulatory T (Treg) cells contribute to immune evasion and are associated with poor prognosis in solid tumors. While CD47 blockade has demonstrated efficacy in hematologic malignancies, its application in solid tumors is hindered by the antigen sink effect and lack of tumor selectivity. Here, we report a rationally designed aptamer-siRNA chimera that selectively targets intratumoral Treg cells by exploiting their co-expression of PD-L1 and CD47 within the tumor microenvironment. The PD-L1 aptamer enables selective binding to PD-L1⁺ Treg cells and simultaneously inhibits PD-L1-mediated immune suppression. Conjugated CD47 siRNA silences CD47 expression, abrogating the "don't eat me" signal and facilitating phagocytic clearance. Mechanistically, this chimera efficiently depletes tumor-infiltrating Treg cells with negligible impact on peripheral cells, and leads to a pronounced increase in intratumoral CD8⁺ T cell infiltration. Further investigation revealed that the chimera impairs Treg migration by disrupting glycolysis-related signaling pathways, including pERK1/2 and pRac1, and induces metabolic reprogramming characterized by reduced glycolysis, increased oxidative metabolism, and elevated fatty acid oxidation (FAO). In murine hepatocellular carcinoma models, treatment with the chimera significantly inhibited tumor growth, reduced angiogenesis, and prolonged survival. Our findings highlight a dual immune checkpoint-targeting strategy that integrates selective delivery with gene silencing, offering a tumor-specific, non-antibody approach for Treg depletion and a promising avenue for solid tumor immunotherapy.

Colorectal cancer (CRC) is one of the most malignant cancers, and studies have indicated that microbes within tumors play a crucial role in CRC. Advanced methodologies, including single-cell and spatial technologies, high-resolution sequencing, and multi-omic integration, are now unraveling the complex composition and function of the intratumoral microbiome. Mechanistically, these microbial communities contribute to CRC initiation by serving as direct mutagens that induce genomic instability, perpetuating a state of chronic inflammation, and activating specific carcinogenic pathways. Furthermore, they actively promote tumor progression and metastatic dissemination through multiple means, including the modulation of key oncogenic signaling pathways, extensive remodeling of the tumor immune microenvironment, and facilitation of a pro-metastatic niche. Given these profound and multifaceted influences, the intratumoral microbiome shows significant promise as a source of diagnostic and prognostic biomarkers, offering considerable potential for non-invasive monitoring and improved risk stratification in clinical practice. Therapeutically, intervention strategies are rapidly evolving, encompassing approaches such as microbiome modulation to enhance conventional therapies, precise clearance of pathogenic bacteria, utilization of intrinsically antitumor microbes, and the engineering of synthetic bacteria as targeted living therapeutics. This review comprehensively outlines the current research methods, elaborates on the mechanistic insights, and discusses the therapeutic targeting of the intratumoral microbiome, aiming to provide a foundational framework for developing new and effective strategies in CRC precision medicine.

High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements constitutes a distinct clinicopathological entity characterized by aggressive behavior, inherent resistance to conventional immunochemotherapy, and suboptimal clinical outcomes. Within our cohort, MYC/BCL2 rearrangements defined double-hit lymphoma (DHL), MYC/BCL6 as DHL-BCL6, and concurrent MYC/BCL2/BCL6 as triple-hit lymphoma (THL). Here, we delineated the clinical characteristics and genetic aberrations of 112 DHL/THL patients to investigate the factors influencing lymphoma relapse and optimize treatment strategies. Compared to 80 DHL-BCL6 patients, DHL/THL manifested distinct features, including an increased prevalence of the germinal center B-cell-like subtype and co-expression of MYC/BCL2, and demonstrated significant associations with abbreviated progression-free and overall survival. Univariate and multivariate analyses identified Ann Arbor stage and serum lactate dehydrogenase elevation as independent prognostic determinants. Therapeutic intensification employing R-DA-EDOCH was correlated with enhanced survival outcomes, while consolidative autologous stem cell transplantation significantly improved prognosis in patients who achieved remission after first-line immunochemotherapy. Regarding genetic aberrations, oncogenic mutations were detected in 102 evaluable patients. EZH2 mutation occurred more frequently in DHL/THL, while TNFRSF14 mutation exhibited greater prevalence in THL. The EZB genotype was predominantly observed in DHL/THL patients, and those with TP53 abnormalities exhibited a further diminished prognosis. In terms of the immune microenvironment, the depleted lymphoma microenvironment (LME-DP) subtype, characterized by diminished immune cell infiltration, demonstrated a propensity for increased frequency in DHL/THL patients. Collectively, these findings advance the comprehensive understanding of DHL/THL pathobiology, underscoring the imperative for novel targeted agents and therapeutic approaches.