From "Simulation" to "Mirror": Gene editing and humanization redefines the next-generation precision oncology animal model.

Characterizing the Discordance between AT-Rich Interacting Domain 1A Protein and Genotype in Endometrioid-Type Endometrial Tumors.

N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine-quinone (6PPD-Q) is an emerging environmental pollutant with limited research on its reproductive toxicity. In this study, female offspring mice were exposed to 6PPD-Q during gestation and lactation. The results revealed that 6PPD-Q exposure disrupted the hypothalamus-pituitary-ovary (HPO) axis in postnatal day (PND) 22 female offspring mice, leading to precocious puberty and estrous cycle irregularities, accompanied by substantial metabolic alterations. At PND 71, disturbances in the HPO axis and metabolic functions were observed. In both in vivo and in vitro experiments, 6PPD-Q was found to suppress hypothalamic gonadotropin releasing hormone (GnRH) secretion via the Kisspeptin/GPR54 pathway, inhibit pituitary luteinizing hormone (LH) and follicle stimulating hormone (FSH) secretion through the PKC/c-Raf/ERK1/2/IEGs pathway, and induce oxidative stress in human granulosa-like tumor cell line (KGN), resulting in a reduction in estradiol (E2) secretion. Collectively, this study provides novel theoretical insights into the potential reproductive toxicity and metabolic impact of 6PPD-Q.

Secondary metabolites from the endophytic fungus Trichoderma afroharzianum and their cytotoxic activities.

The duality of testosterone in glioblastoma: From targeted therapy to modulation of the tumor microenvironment and neuroprotection.

Undescribed triterpenoid ellagitannins from Castanopsis calathiformis and their potential antiproliferative and hypoglycemic activity.

Limited involvement of MMP2, MMP9 and MMP14 in vasculogenic mimicry formation of human tumor cell lines.

Standard treatment for locally advanced rectal cancer involves neoadjuvant chemoradiation therapy (nCRT) followed by total mesorectal excision, but this approach carries significant morbidity and often results in incomplete resections owing to poor intraoperative tumor visualization. For patients with complete response to nCRT, a watch-and-wait (W&W) strategy can spare surgery, but current imaging techniques inadequately identify complete responders, leading to regrowth in ~30% of cases. To improve nCRT response assessment and guide resections, we developed PH10, a topically applied, pH-activatable near-infrared (NIR) fluorescent probe for rapid, tumor-specific imaging. PH10, a small-molecule cyanine analog, was tested in murine models and on human tumor specimens (n = 11). Fluorescence activation, tumor specificity, and tumor-to-background ratio (TBR) were evaluated in vivo and ex vivo within clinically relevant timeframes. PH10 enabled rapid and specific tumor visualization, achieving a median TBR of 3.2 within 1 min in vivo in murine models and 2.2 within 10 min ex vivo on human samples. The probe demonstrated high specificity for tumor tissue within the acidic tumor microenvironment without requiring systemic administration or prolonged incubation. PH10 is a promising, fast-acting topical NIR agent for real-time tumor detection during colorectal cancer endoscopy and surgery. Its simplicity and rapid kinetics support potential clinical translation. Moreover, its pH-activatable mechanism may extend its utility to other solid cancers with acidic microenvironments.

Despite promising development as emerging "off-the-shelf" therapeutics against cancer, natural killer (NK) cells still faced considerable challenges in the solid tumor microenvironment (TME), including poor penetrance and immuno-suppression. Here, we employ spatial and single-cell transcriptomics to reveal a role for Nur77 in NK cell-mediated immunity against hepatocellular carcinoma (HCC). Orthogonal analysis of human and mouse HCC tumors indicate that the expression of NR4A1, encoding Nur77, is associated with NK cell proliferation, activation of the immunostimulatory AP-1 gene regulons, and better disease-free survival in HCC. Conditional ablation of Nr4a1 in NK cells perturbs their homeostasis and accelerates tumor progression in multiple tumor models. Conversely, the agonistic activation of Nur77 in NK cells ex-vivo or in-vivo enhances their anti-tumor functions. Mechanistically, downstream functional assays confirm that Nur77 activation attenuates CD36 expression in NK cells and confers resistance against oxLDL-mediated immunosuppression in the TME. Collectively, our findings highlight the potential of harnessing Nur77 agonism in improving NK cell-based immunotherapy against HCC.

The immune checkpoint protein B7H4 is overexpressed in tumors compared to normal tissues, making it an attractive target for cancer immunotherapy. Here, we compare two B7H4-targeting CD3 bispecific antibodies (bsAbs) with different CD3 affinities across in vitro and in vivo characterization studies. In vitro, the CD3xB7H4 bsAb variant with higher CD3 affinity showed greater potency for tumor cell killing and cytokine secretion than the lower affinity variant. In nonclinical toxicology assessments in cynomolgus monkeys, the CD3xB7H4 bsAb variant with lower CD3 affinity induced less cytokine secretion and was tolerated at a higher maximum plasma concentration. Both CD3xB7H4 bsAbs demonstrated antitumor activity in vivo in an ovarian cancer patient-derived xenograft (PDX) mouse model and ex vivo in dissociated primary human ovarian tumor samples. These results demonstrate that increased CD3 affinity enhances cytotoxic potency but results in cytokine secretion at lower antibody concentrations in vitro and in vivo, highlighting an important design trade-off in CD3 bsAb development. The therapeutic potential of CD3xB7H4 bsAbs, particularly in relation to CD3 affinity, warrants further investigation in the clinic.

Organoid technology has emerged as a transformative tool in cancer research by recapitulating the structural complexity, genomic integrity, and phenotypic heterogeneity of human primary tumors. Over the past 15years, this technology has transcended the limitations of traditional preclinical cancer models, evolving from a specialized developmental biology technique into a versatile platform that spans basic mechanistic research, translational drug development, and clinical personalized medicine. This review provides a comprehensive and in-depth overview of organoid systems, spanning fundamental biological principles, standardized methodologies for tumor organoid establishment, and multi-dimensional applications across the entire cancer research continuum. We highlight mechanistic insights into tumor initiation, clonal evolution, progression, and metastatic colonization revealed by organoid models, as well as translational advances in high-throughput drug discovery, functional precision oncology, immuno-oncology therapeutic development, and early cancer detection and interception. Particular emphasis is placed on therapeutic development strategies and recent prospective clinical trials validating patient-derived organoids (PDOs) as predictive functional biomarkers for treatment response, which represents the most critical translational milestone in the field. By integrating cutting-edge single-cell multi-omics technologies, spatial profiling, and bioengineering advances, we further discuss current limitations, unresolved technical and biological challenges, and future directions aimed at bridging the long-standing gap between bench research and clinical practice. This work aims to present an updated, clinically oriented synthesis of organoid applications in oncology, with the ultimate goal of accelerating the clinical translation of organoid technology to advance precision cancer care and improve patient outcomes.

Receptor tyrosine kinases are key regulators of various fundamental cellular processes, and dysregulation of their activities may lead to many human diseases including cancer. EphA2 is a member of the Eph subfamily of receptor tyrosine kinases that play an important role in regulating tissue patterning, homeostasis, and regeneration. Accumulating evidence indicates that EphA2 is a critical regulator of cancer development and progression and can function as both a tumor suppressor and an oncogenic driver. When acting as an oncogenic driver, EphA2 can promote tumor initiation, growth, invasion, metastasis, stemness, and angiogenesis by activating or enhancing the oncogenic signaling pathways. High expression of EphA2 in a wide range of human tumor tissues is closely associated with poor prognosis, thus it is a very promising target for cancer treatment. A number of studies on EphA2-targeted cancer treatment are currently at the clinical trial stage. In this review, we discuss the oncogenic roles and mechanisms of action of EphA2 in cancer development and progression, which could provide novel insights into EphA2-targeted cancer treatment.

Selecting appropriate preclinical models is fundamental for translational oncology, yet a large-scale, multi-omic quantitative comparison of their similarity to primary human tumors is lacking. To address this, we integrated transcriptomic, proteomic, and genomic profiles from over 10,000 primary tumors from The Cancer Genome Atlas (TCGA) and the Clinical Proteomic Tumor Analysis Consortium (CPTAC), alongside 4,000 preclinical models. Using a robust computational framework, we revealed a clear hierarchy of transcriptomic and proteomic similarity to patient tumors: patient-derived xenografts (PDXs) > patient-derived organoids (PDOs) = PDX-derived organoids (PDXOs) > cell lines. We also quantified high molecular conservation (Pearson correlation coefficient = 0.96) across paired in vitro to in vivo platform (organoids to PDX) transitions. Furthermore, genomic analysis demonstrated that whole-exome sequencing (WES) outperforms RNA sequencing (RNA-Seq) in detecting DNA variants, and it identified a clonal complexity hierarchy (cell lines > PDXOs > PDXs > PDOs) reflecting the impact of passaging history on intra-tumor heterogeneity. Ultimately, this study delivers a comprehensive quantitative benchmark, establishing a population-level hierarchy of molecular similarity between preclinical models and primary tumors, and providing a data-driven reference for model selection. These findings offer a data-driven framework for selecting models that balance biological representativeness with experimental practicality.

Organoid-based platforms for oncolytic virus discovery and optimization: Bridging in vitro innovation and clinical translation.

Long non-coding RNAs (lncRNAs) regulate gene expression at different levels, and their abnormal expression is involved in tumor development and progression. Long intergenic non-coding RNA 1614 (LINC01614) has attracted increasing interest because it is aberrantly expressed in several cancer types. This narrative review summarizes current evidence on LINC01614 in cancer biology, with a focus on cancer progression, therapy response, and its possible relevance to precision medicine. PubMed, Web of Science, and Google Scholar were searched from database inception to May 18, 2026. The search terms included "LINC01614," "lncRNA," "cancer," "biomarker," "therapy response," and "therapy resistance." LINC01614 is frequently dysregulated in solid tumors. Available studies have linked it to cancer cell growth, migration, invasion, apoptosis regulation, metabolic changes, and therapy response. The evidence is uneven across tumor types. Some mechanisms are supported by functional assays and rescue experiments, whereas others mainly rely on public datasets, risk models, or small tissue cohorts. LINC01614 should be viewed as an emerging cancer-related lncRNA, not as a fully validated driver across all cancers. This review summarizes the reported roles of LINC01614 in cancer progression and therapy response. Current evidence suggests that LINC01614 may regulate cancer-related pathways in a tumor-dependent manner. Its clinical value needs to be further defined by larger cohorts, direct mechanistic studies, and models that better reflect human tumors.

The Hippo pathway prevents tissue overgrowth and tumorigenesis in many organs across species. Not surprisingly, this pathway limits the proliferation of progenitor cells in diverse regions of the nervous system, and its dysregulation can lead to neural tumors in humans. However, the functions of the Hippo pathway extend beyond proliferation control. Recent studies have revealed a remarkable functional diversity across neural lineages, encompassing morphogenesis, cell fate, tissue maintenance, and repair. This review synthesizes current evidence on the roles and regulation of the Hippo pathway in neural progenitor cells, glial cells, and neurons, highlighting context-dependent mechanisms and outstanding questions. With the core molecular machinery and many fundamental cellular functions of the Hippo pathway now established, the field is entering a new phase: unraveling the functional significance and regulatory complexity of Hippo signaling in physiologically relevant contexts-both normal and diseased-promises to deepen our mechanistic understanding of neural development and homeostasis, and unlock new strategies for tumor therapy and neural repair.

Ubiquitination represents a promising therapeutic target for age-associated diseases, yet its functional role in ovarian aging remains poorly defined. This study systematically characterizes ubiquitinated proteins in luteinized granulosa cells (GCs) from women of advanced maternal age (AMA), aiming to provide molecular insights into the ubiquitination-dependent regulatory network underlying ovarian aging and further elucidate the mechanisms governing energy metabolism reprogramming in senescent GCs. A total of 60 patients undergoing their first in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) were recruited in this study, including 30 patients with young maternal age (YMA) and normal ovarian reserve, and 30 patients with advanced maternal age (AMA) and ovarian aging. The recruitment period was from November 2024 to May 2025. Nine samples of luteinized GCs were randomly selected from each group for ubiquitinated proteomic sequencing analysis. Functional exploration of differentially ubiquitinated proteins was performed via Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Protein-protein interaction (PPI) network analysis was conducted to identify molecular targets of potential pathways. Additionally, the ubiquitination level and protein expression of alpha-enolase (ENO1) were validated by immunoprecipitation Western blot (IP-WB) and Western blot (WB) assays, respectively. Furthermore, an in vitro oxidative stress-induced ovarian aging model was established using hydrogen peroxide (H₂O₂)-treated human granulosa-like tumor cells line (KGN cells) to further investigate the regulatory role of ENO1 in energy metabolism reprogramming of GCs during ovarian aging. A total of 174 ubiquitinated peptides with significant differences were screened between the two groups (|log₂ FC|> 1, q < 0.05). Compared with the YMA group, 80 ubiquitinated peptides were significantly upregulated and 94 were significantly downregulated in the AMA group. GO enrichment analysis revealed that differentially ubiquitinated proteins (DUPs) were enriched in the "metabolic pathways" of biological processes (P < 0.05). Further KEGG pathway analysis suggested that the "ubiquitin-mediated protein degradation" and "proteasome" pathways may be involved in the regulation of ovarian aging. In addition, DUPs exhibited differential ubiquitination characteristics in energy metabolism pathways: the ubiquitination levels of proteins related to the "tricarboxylic acid (TCA) cycle" pathway were upregulated, while those related to the "glycolysis" and "pentose phosphate pathway (PPP)" were downregulated (P < 0.05). PPI network analysis indicated that ENO1, a differentially ubiquitinated protein (FDR < 0.05) and a key glycolytic enzyme, may serve as a critical target for energy metabolism reprogramming during ovarian aging. WB and IP-WB results showed that the ubiquitination level of ENO1 was downregulated in AMA GCs, whereas its protein expression level was elevated. Functional experiment results demonstrated that ENO1 inhibitors could attenuate H₂O₂-induced senescence of KGN cells, downregulate p16 expression, and improve the activity of key glycolytic enzymes as well as metabolite levels. No significant change was observed in ENO1 mRNA levels, suggesting that its expression is mainly regulated by post-transcriptional modifications such as ubiquitination. This study demonstrates that DUPs between the AMA and YMA groups exhibit distinct ubiquitination patterns in energy metabolism pathways: the ubiquitination levels of proteins associated with the "TCA cycle" pathway are upregulated, whereas those related to "glycolysis" and the "PPP" are downregulated. ENO1, a key enzyme in glycolysis, is subject to ubiquitination-mediated post-transcriptional regulation. Inhibition of ENO1 can alleviate GC senescence and improve the abnormal glycolytic phenotype. In summary, ubiquitination modification may be involved in the process of ovarian aging, and targeting ENO1 ubiquitination to regulate energy metabolism reprogramming is expected to provide a potential intervention target for improving reproductive outcomes in AMA.

Epithelial ovarian cancer (EOC) is a lethal malignancy with high recurrence rates owing to residual micrometastases and chemoresistance. This study explores cytoskeletal regulation as a potential therapeutic strategy to modulate tumor cell fate. We demonstrate that combining (‒)-Blebbistatin (Ble) with adipogenic stimuli (BMP4 or PPARγ agonists) effectively induces adipogenic transdifferentiation of ovarian cancer cells both in vitro and in vivo. The transformed cells exhibit characteristic lipid droplet accumulation, upregulated adipogenic markers (PPARG, CEBPA, and FABP4), and functional maturation evidenced by β-adrenergic-responsive lipolysis. In subcutaneous and intraperitoneal models, Ble treatment significantly suppressed tumor growth, with HuNu/Perilipin 1 colocalization confirming human tumor cell conversion into adipocyte-like cells. Mechanistic investigations reveal that cytoskeletal destabilization triggers nuclear heterochromatin redistribution and chromatin decondensation, enhancing accessibility for adipogenic transcription factors (CEBPA and CEBPB) to activate related transcriptional programs. The critical role of mechanical signaling is demonstrated by both adipogenic conversion on soft substrates and the prevention of Ble-triggered adipogenesis following overexpression of a constitutive nuclear localization mutant of YAP. These findings establish that cytoskeletal destabilization in combination with adipogenic instructive cues enable the adipogenic reprogramming of EOC cells via heterochromatin remodeling, providing preclinical insights for ovarian cancer differentiation-targeted therapy.

Rational design and synthesis of pyrazole-based sulfonamides as dual carbonic anhydrase and PRAK-targeting anticancer agents.

Brain metastases (BrM) remain a major cause of mortality in breast cancer (BC), yet the spatial organization and molecular circuitry of the metastatic immune microenvironment are poorly defined. To address this gap, we integrated high-plex imaging mass cytometry (IMC) performed on human primary breast tumors (n=20 regions of interests (ROIs)) and human brain-metastasis tissues (n=40 ROIs) with publicly available datasets, including single-cell RNA sequencing (scRNA-seq) from BC (n=10) and BrM (n=12) and spatial transcriptomic (ST) data from BC (n=7) and BrM (n=1), enabling single-cell resolution of tissue architecture, functional states, and intercellular signaling. IMC resolved nine major cell classes and diverse epithelial, myeloid, and T-cell subtypes, and revealed a striking shift in macrophage polarization: CD163-CD11b- macrophages were markedly depleted in brain metastases, whereas CD163+ subsets persisted. Spatial analysis demonstrated the loss of the immune-permissive CN1 neighborhood in brain metastases, which is enriched in memory T cells, B cells, and dendritic cells, and the expansion of the immunosuppressive CN9 niche in brain metastases, containing CD163+ macrophages, invasion-like epithelial cells, and exhausted T cells. ScRNA-seq integration corroborated these findings by refining the annotation of major immune and stromal lineages and confirming CD163 expression patterns across macrophage subsets. ST deconvolution further reproduced these CN1-like and CN9-like domains in situ, validating their anatomical organization across BC and BrM. Ligand-receptor inference highlighted specific inhibitory pathways-including programmed cell death protein 1/programmed death-ligand 1, growth arrest-specific 6-Tyro3, Axl, and Mer receptor tyrosine kinase family, nectin cell adhesion molecule 2 (NECTIN2)-T-cell immunoreceptor with Ig and ITIM domains, and prostaglandin E2 (PGE2)-prostaglandin E2 receptor 4-that are associated with immune evasion and metastatic growth. Functional validation in an in vivo brain metastasis model further supported the therapeutic relevance of targeting these immunoregulatory pathways. Together, these findings show a shift from permissive to suppressive immune niches, accompanied by pronounced macrophage reprogramming, as central features of BC adaptation to the brain. This spatially resolved framework provides mechanistic insight into the poor responsiveness of brain metastases to current immunotherapies and identifies defined inhibitory ligand-receptor axes as actionable targets for combination immunotherapy.