Dynamic nanomachines capable of selectively engaging tumor-infiltrating immune cells and modulating their intrinsic functions represent a critical unmet need in cancer immunotherapy. Here, we develop an intelligent DNA nanomachine that selectively targets dendritic cells (DCs) within the tumor microenvironment and modulates their immunological function through regulation of prosaposin glycosylation. The nanomachine is constructed on a tetrahedral DNA nanostructure (TDN) and integrates an acid-responsive strand displacement cascade. Selective activation of this cascade in the acidic tumor microenvironment exposes a DC-SIGN-binding aptamer, thereby enabling preferential engagement with tumor-infiltrating DCs. In parallel, the nanomachine initiates RNA interference to silence St6Gal1, leading to suppression of aberrant prosaposin hyperglycosylation in melanoma-associated DCs. This spatiotemporally controlled modulation minimizes off-target interference with immune cells in normal tissues, restores the functional competence of intratumoral DCs, consequently enhances intratumoral T-cell infiltration, and markedly suppresses melanoma growth in mice. Collectively, this work establishes a programmable, strand-displacement-driven DNA nanomachine that integrates tumor microenvironment-triggered DC targeting with glycosylation-directed functional modulation, offering a generalizable strategy for precise remodeling of the tumor immune microenvironment.

GLI1-altered mesenchymal tumors are exceptionally rare mesenchymal tumors, with recent molecular studies implicating GLI1 gene fusion or amplification. We report a 39-year-old nonsmoking woman who presented with an incidentally detected right pleural-based mass. Cross-sectional imaging identified a paraspinal pleural lesion at the T5-T6 level without intraspinal extension. Video-assisted thoracoscopic resection revealed a biphasic tumor and next-generation sequencing confirmed an ACTB-GLI1 fusion. The diagnosis of GLI1-altered mesenchymal tumor was established. After multidisciplinary discussion, the patient opted for radiologic surveillance instead of adjuvant therapy. She remains disease-free at 1-year follow-up. This case expands the anatomic spectrum of GLI1-altered tumors and underscores the value of molecular testing in distinguishing them from other pleural neoplasms.

Mycosis fungoides (MF) is the most common type of primary cutaneous T-cell lymphoma, a disease characterized by malignant T cells that home to the skin. In early stages, clinical presentation is often indistinguishable from benign chronic inflammatory skin diseases such as atopic dermatitis (AD), posing a challenge for proper diagnosis and treatment. Previous studies have established that MF is characterized by the expansion of a single T-cell clone, whereas benign skin conditions are polyclonal in nature. In this study, we aimed to use single-cell RNA sequencing data to detect distinct transcriptomic features of early-stage MF in comparison to AD skin. In early-stage MF, we observed gene expression differences in cells of both the stroma and the immune system, with keratinocytes exhibiting increased interferon response and proliferation (STAT1, ICAM1, HLA-DRA, GJB2), while fibroblasts displayed tumour-associated programs (CXCL2, TNFAIP6, CEBPD). Myeloid cells exhibited expression of immunomodulatory genes (RUNX3, DDIT4, IL4I1), and malignant T-cells expressed exhaustion-associated markers (CXCL13, SOCS3, F2R, ETV1), as opposed to AD and healthy control samples. Thus, our results provide a novel insight into the immune-stroma crosstalk in the tissue microenvironment of early-stage MF vs. AD skin lesions.

Emerging evidence highlights the critical role of metabolic pathways in breast cancer (BC) progression. Here, we developed a butyrate metabolism-specific gene (BMRG) signature to predict clinical outcomes and immunotherapy responses in BC, providing a novel pathway-focused prognostic tool. Using data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), we identified 102 butyrate metabolism-related differentially expressed genes (DEGs) through the intersection of DEGs, WGCNA-derived key module genes, and BMRGs. Univariate Cox followed by least absolute shrinkage and selection operator (LASSO) analysis identified nine genes to construct a prognostic signature, which served as an independent prognostic factor. Risk stratification revealed distinct immune microenvironment and mutation landscapes between subgroups, with risk scores strongly correlating with immune checkpoint expression. The signature exhibited robust prognostic performance, with AUC values for 3-, 5-, and 7-year overall survival ranging from 0.65-0.69 in TCGA and 0.57-0.77 in independent GEO cohorts. Protein-protein interaction analysis identified ACSL1 as a key hub gene, and functional validation confirmed that ACSL1 knockdown suppressed BC cell proliferation and migration. Our findings establish this novel nine-gene butyrate metabolism-specific signature as a promising prognostic biomarker and potential therapeutic target for BC, providing a metabolism-focused perspective for personalized BC management.

Most tumors exhibit increased glucose uptake and reprogram metabolism to aerobic glycolysis to meet their demands for macromolecule biosynthesis and energy production. Consequently, PET/CT using 18F-2-fluoro-2-deoxy-D-glucose (18F-FDG-PET/CT) has been developed and is clinically utilized in cancer imaging diagnostics. However, numerous cancers demonstrate negative imaging during 18F-FDG-PET/CT detection, suggesting these cancers employ alternative metabolic rewiring. In this study, we discovered that 18F-FDG-PET/CT-negative gastric cancers coordinate glutamine-based gluconeogenesis and fatty acid oxidation to meet DNA and ATP demands, sustaining tumor growth despite low glucose uptake. PCK and CPT1A, the key enzymes which are responsible for remodeling the metabolism, were highly expressed in FDG-PET/CT-negative gastric cancers. Accordingly, PCK/CPT1A negatively correlated with 18F-FDG imaging levels and positively correlated with poorer clinical classifications. Mechanistically, PPARγ is highly expressed in FDG-PET/CT-negative cells and drives the transcription of the PCK and genes. Pharmacological inhibition of the PCK/CPT1A significantly suppressed tumor growth in 18F-FDG-PET/CT-negative gastric cancers, as demonstrated in both cell-derived xenograft (CDX) and patient-derived xenograft (PDX) models. Together, these results highlight the heterogeneity of tumor cells from metabolic perspective, and identify PCK/CPT1A as a target for metabolic reprogramming and precision therapy of 18F-FDG-PET/CT-negative cancers.

Diffuse midline gliomas (DMG) are deadly pediatric brain cancers with limited treatment options. These tumors likely arise from oligodendrocyte precursor cells (OPC) that acquire a driver histone mutation, leading to an aberrant epigenome. RNA N6-methyladenosine (m6A) is a vital epi-transcriptomic modification that regulates RNA processes and plays a significant role in OPC development through its regulation of transcripts involved in histone modification processes. Despite this pivotal role in OPC biology, the epi-transcriptome has not yet been investigated in DMG, and its interrogation may uncover new therapeutic options and understanding of this disease. Therefore, for the first time, we generated base-resolution m6A landscapes for patient-derived DMG cultures and found that DMG exhibits elevated m6A levels compared to non-neoplastic patient cells, with particularly strong enrichment on transcripts involved in cell motility and migration. In contrast, the minority of transcripts that have lower levels of m6A in DMG were associated with cell cycle regulation, especially components of chromosome segregation machinery. We also demonstrate that DMG is sensitive to inhibition of the m6A demethylase FTO, with FB23-2 treatment resulting in decreased proliferation, reduced survival, and pronounced S-phase arrest/stress, accompanied by robust induction of CDKN1A, GADD45B, and TFRC. Furthermore, FTO inhibition led to significant downregulation of key cell cycle regulators at both the transcriptomic and proteomic levels. Collectively, these findings highlight RNA methylation as a critical regulator of DMG tumorigenicity and identify FTO as a promising therapeutic target for this currently incurable disease.

Drug resistance jeopardizes the prognosis of high-grade serous ovarian carcinoma (HGSOC) patients via DNA damage repair-coupled mechanism. The role of biomolecular phase separation in DNA damage repair has loomed. Here we find that CBX2 condensates are associated with drug resistance and contribute to DNA double-strand break (DSB) repair in HGSOC. Specifically, CBX2 condensates facilitate the recruitment of key DSB repair factors PARP1, 53BP1, and BRCA1 to chromatin. Patients with a CBX2-negative pattern exhibit the best prognosis, followed by those with non-condensate CBX2, while the worst outcomes are observed in patients with condensate CBX2. By drug screening, Ibrutinib is identified as an effective inhibitor of HGSOC cells and patient-derived organoids with CBX2 condensates. Overall, CBX2 phase separation enhances DSB repair-mediated drug resistance in HGSOC cells, and Ibrutinib may offer a viable therapeutic option for CBX2-positive HGSOC patients.

Reprogramming of lipid metabolism and cyclic GMP‒AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling is associated with cancer development. However, whether and how fatty acid metabolism regulates the cGAS‒STING pathway in colorectal cancer (CRC) remains to be elucidated. In this study, we found that short-chain acyl-CoA dehydrogenase (ACADS) is aberrantly deficient in CRC cells and is associated with cancer progression in human patients. We further revealed that ablation of ACADS promoted CRC progression by orchestrating the cGAS‒STING signaling-dependent immunosuppressive tumor microenvironment (TME) in mouse xenografts and AOM/DSS-induced CRC models. Mechanistically, ACADS deficiency suppressed cGAS‒STING signaling by inhibiting mtDNA leakage in a nonmetabolic manner. ACADS binds to and inhibits mitochondrial DNMT1 (mito-DNMT1)-dependent mtDNA methylation, thereby stabilizing mtDNA and inhibiting its leakage. Genetic and pharmacological modulation of mito-DNMT1 restored ACADS-regulated mtDNA leakage, cGAS‒STING signaling, and CRC progression. Importantly, strong correlations between ACADS, mito-DNMT1, and STING signaling and the immune TME were found in patients with CRC. Furthermore, we screened and identified an old drug, hypericin, as an ACADS-binding compound that upregulates ACADS expression. Hypericin treatment can mimic ACADS overexpression-regulated pathways, ultimately improving the immune TME and suppressing CRC growth. These findings highlight a previously undiscovered ACADS/mito-DNMT1 complex that links fatty acid metabolism reprogramming to mtDNA methylation and cGAS‒STING signaling-dependent antitumor immunity.

Adipokines secreted by adipocytes have emerged as critical modulators of cancer progression, particularly in obesity-associated malignancies. However, their therapeutic relevance and the tumor types responsive to adipokine pathways remain unclear. To identify adipokine-driven cancers and assess the therapeutic potential of adipokine signaling, we conducted a pan-cancer transcriptome analysis of the expression of various adipokine receptors in 31 tumor types. AdipoR1 was most frequently amplified and overexpressed in breast cancer across molecular subtypes. In the functional analysis, AdipoR1 stimulation using the agonist AdipoRon activated AMPK signaling, suppressed proliferation and migration, and induced apoptosis in both hormone receptor (HR)-positive (MCF7, T47D) and triple-negative (MDA-MB-231, MDA-MB-468) breast cancer cells. Notably, RNA-Seq analysis revealed that AdipoR1 stimulation upregulated ferroptosis-related genes, DDIT3, HMOX1, and IRE1α, and downregulated proliferation-related genes, estrogen receptor and TROP2, in breast cancer cell lines. Immunoblotting confirmed these changes at the protein level. AdipoR1 activation enhanced the efficacy of chemotherapeutic agents. In vivo, AdipoRon significantly reduced tumor growth and induced necrotic cell death. AdipoR1 activation exerts multimodal antitumor effects by engaging cell death and hormone receptor signaling. These findings establish AdipoR1 as a valuable therapeutic target in breast cancer and support further development of adipokine receptor-targeting therapies.

Micronuclei are small, independent cytoplasmic structures containing nuclear material. They typically form during cell division due to DNA damage or division abnormalities, serve as biomarkers of genetic damage, and are closely associated with chromosomal instability (CIN). Emerging evidence suggests that micronuclei actively promote and exacerbate CIN, with significant implications in disease pathology and potential therapeutic applications. This review provides a comprehensive overview of micronuclei by exploring their origins, formation mechanisms, and functional consequences, and detailing the fate of micronuclei post-formation, which is essential for elucidating their role in genomic instability and potential therapeutic implications. Furthermore, micronuclei can contribute to extreme chromosomal shattering and genomic instability. These processes are increasingly recognized as critical contributors to disease progression, particularly in cancer. Although micronuclei have traditionally been viewed as markers of genomic instability, recent evidence suggests that they may also serve functional roles. Their potential use as treatments for certain diseases appears theoretically feasible; however, challenges remain in selectively targeting cells to induce the formation of favorable micronuclei and maintain optimal immune responses. Addressing these questions could open new avenues for therapeutic interventions.

Colorectal cancer (CRC) is a leading cause of cancer-associated deaths, with liver metastases developing in about 50% of patients. Mitochondrial dynamics play critical roles in a diverse range of cellular functions, including cell migration and cancer metastasis. However, the influence of mitochondrial dynamics deregulation in CRC liver metastasis is incompletely understood. Through multiple transcriptomic data analysis and validation, we found that low expression of SNPH significantly correlated with poor prognosis of CRC patients. SNPH knockdown altered mitochondrial dynamics to increase cell migration and invasion by promoting filopodia formation. Moreover, the reduced levels of SNPH were linked to HIF-1α expression. Luciferase reporter assay revealed that HIF-1α transcriptionally activated miR-130a-3p expression, which targeted SNPH mRNA to inhibit its protein levels. Furthermore, miR-130a-3p inhibitor suppressed SNPH downregulation, filopodia formation, and CRC cells metastasis under hypoxic conditions. Mechanistically, SNPH downregulation promoted ROS production, resulting in the activation of the AKT/cdc42 pathway and downstream PAK1/Cofilin cascade. The overexpression of SNPH increased mitochondrial fusion and deterred the liver metastasis ability of CRC cells in vivo. Together, our results suggest that SNPH suppression imposed by the HIF-1α/miRNA-130a-3p axis under hypoxia conditions promotes the liver metastasis of CRC cells by activating the AKT/cdc42-PAK1/Cofilin cascade through mitochondrial dynamics-mediated ROS production.

Aberrant alterations in transcription factors often disrupt key signalling pathways, contributing to oncogenesis in multiple cancers, including breast cancer. Spalt-like (SALL) transcription factors are a highly conserved family of proteins with distinctive zinc finger motifs that are emerging as crucial players in tumorigenesis. Despite their pivotal roles in oncogenesis, limited studies have been carried out to explore their roles specifically in breast cancer.

L1 cell adhesion molecule (L1CAM) has emerged as a potential prognostic biomarker in endometrial cancer. This systematic review and meta-analysis aimed to comprehensively evaluate the prevalence of L1CAM expression across molecular subtypes of endometrial cancer and its prognostic significance for survival outcomes.

Bulk RNA sequencing (bulk RNA-seq) and single-cell RNA sequencing (scRNA-seq) are two important high-throughput sequencing platforms that have wide applications in biomedical research. Bulk RNA-seq reflects the average gene expression of all cells in the sample at a low experimental cost, whereas scRNA-seq enables transcriptomics profiling at a single-cell level, although with higher experimental costs. To integrate the strengths of both sequencing approaches and capitalize on the wealth of existing bulk RNA-seq datasets, we developed a U-Net-based deep learning algorithm, BLUE, to deconvolve bulk RNA-seq samples into cell-type proportions and cell-type-specific gene expression profiles. Built upon a U-Net backbone, BLUE leverages its powerful feature extraction and representation learning capabilities to achieve accurate predictions for cell-type-specific gene expression profiles, which significantly outperform existing deconvolution algorithms. Given the accurate prediction from BLUE, we developed an integrative framework for subtyping cancer patients and identifying cell-type-specific gene signatures that can function as prognostic biomarkers for cancer.

Cancer progression involves coordinated regulation of oncogenes and tumor suppressors. This study explores the interplay of ENOX2 (ecto-NADH oxidase disulfide-thiol exchanger 2), MMP2 (matrix metalloproteinase-2), and regulatory genes Ras Association Domain Family Member 1, Isoform A (RASSF1A), WAP Four-Disulfide Core Domain Protein 10A (WFDC10A), and Methyltransferase-Like Protein 7A (METTL7A) across multiple cancer cell lines, and evaluates the anticancer potential of repurposed mebendazole.

Pancreatic ductal adenocarcinoma (PDAC) is highly treatment resistant and characterized by a hypoxic microenvironment. Here, we investigated the role of hypoxia-inducible factor 1α (HIF1α) in regulating resistance to radiation and KRAS-inhibitor. We employed CRISPR/Cas9 to knock out (KO) HIF1α from the murine KRASG12D/+; p53R172H/+ KPC and the KRASG12D/+; p53R273H; CDK2NA-/- Panc-1 human pancreatic cell lines. Compared to WT, the HIF1α KO cell lines demonstrated a shift toward an epithelial phenotype and had decreased proliferation and migration under hypoxia. HIF1α KO cell lines were less likely to survive after radiotherapy, and neutral comet assays demonstrated DNA damage four hours after treatment, suggesting that HIF1α promotes radioresistance through non-homologous end joining. When treated with a KRASG12D inhibitor, HIF1α KO cells exhibited significantly increased apoptosis due to decreased p53 degradation, likely mediated through Mdm2. Confirming this, enrichment of hypoxic signaling was associated with KRAS inhibitor resistance in a cohort of 31 KRASG12D cell lines. Our results thus suggest that inhibiting HIF1α may sensitize PDAC to radiation and KRAS inhibitors. To explore this, we conducted a drug repurposing screen and identified three HIF1α inhibitors (bakuchiol, BAY-87-2243, 2-methoxyestradiol) whose sensitivities were correlated with sensitivity to Deltarasin, a KRAS inhibitor. Our findings suggest that HIF1α inhibitors could be used to sensitize PDAC to radiotherapy and KRAS inhibitors.

Drug chemoresistance remains a major reason of treatment failure in cancer patients. In head and neck squamous cell carcinoma (HNSCC), the seventh most common cancer worldwide, cisplatin chemotherapy remains the gold standard for advanced tumors but often faces loss of responsiveness and the drawback of relapse. We previously showed that the metabolic and angiogenic factor angiopoietin-like 4 (ANGPTL4) is a molecular biomarker of oral dysplasia and HNSCC. We also found that through interaction with Neuropilin 1 (NRP1), ANGPTL4 activates proliferative and migratory pathways that contribute to HNSCC development. Using HNSCC xenografts, patient tumor-derived organoids, tumor spheroids, and HNSCC cell lines, CAL27, HN13, and HN4, here we provide evidence of the role of ANGPTL4 in the development of platinum-based chemoresistance in HNSCC through the promotion of DNA damage response (DDR) and homologous recombination (HR). ANGPTL4 enhanced these mechanisms by promoting phosphorylation of RAD51 recombinase in Tyr315/54 through an NRP1/ABL1-dependent mechanism. Pharmacologic inhibition of NRP1 or ABL1 reversed ANGPTL4-mediated DDR and HR, and increased HNSCC cell death in combination with cisplatin, in vitro and in vivo. Our results reveal a role for ANGPTL4 in RAD51-dependent DNA repair and suggest that ANGPTL4/NRP1/ABL1/RAD51 may serve as an alternative therapeutic target for HNSCC.

The World Health Organization introduced substantial revisions in the 2020 fifth edition of the classification system for bone and soft-tissue tumors, reorganizing what were previously called the Ewing sarcoma family of tumors or Ewing-like sarcomas into a new category of "undifferentiated small round cell sarcomas" based on molecular genetic characteristics. This reclassification established four distinct entities: Ewing sarcoma (ES), CIC-rearranged sarcoma, sarcoma with BCOR genetic alterations, and sarcoma with EWSR1-non-ETS fusion genes. Each subtype may demonstrate specific clinical, pathologic, and imaging features, with different treatment responses and prognoses. ES primarily affects children and young adults, with characteristic "moth-eaten" lytic bone destruction, aggressive periosteal reactions, and extensive surrounding soft-tissue masses. CIC-rearranged sarcomas typically manifest as well-circumscribed lobulated soft-tissue masses with extensive internal necrosis and hemorrhage but no calcification. Sarcomas with BCOR genetic alterations commonly occur in adolescent boys as osteolytic or sclerotic lesions in the long bones or the pelvis, often with calcification in the extraosseous component. Sarcomas with EWSR1-non-ETS fusion genes may manifest as osteolytic lesions with cortical expansion and saucer-like surface erosion in long bone diaphyses. Radiologic recognition of CIC-rearranged sarcomas enables oncologists to anticipate their aggressive nature and poor response to standard ES treatments, which may necessitate more intensive initial surgical interventions. In comparison, identifying BCOR-CCNB3 sarcomas through imaging allows clinicians to inform patients of their potentially more favorable outcomes compared with those of ES while still applying appropriate comprehensive treatment approaches. The authors provide an overview of the clinical features, pathologic findings, imaging characteristics, differential diagnosis, and treatment outcomes of each entity. ©RSNA, 2026.

Neocentromeres are newly formed chromosomal regions that can replace the function of traditional centromeres and are well documented in human clinical studies. However, their occurrence in neoplasia, including acute leukemia, appears to be rare. We analyzed complex karyotypes in bone marrow cells from 113 patients with acute myeloid leukemia and one patient with acute lymphoblastic leukemia using centromeric/multicentromeric fluorescence in situ hybridization and identified four cases (3.5%) with derivative chromosomes exhibiting newly formed constrictions. Three of these patients had secondary leukemia following preexisting hematological disorders, suggesting a potential role for neocentromeres in disease progression. In all four cases, neocentromeres were detected on derivative chromosome 11. To our knowledge, this is the first report of neocentromeres derived from this chromosome in acute leukemia. All four patients in our study died; however, all exhibited complex karyotypes, which are independently associated with poor prognosis and an aggressive disease course. Neocentromeres are a rare but potentially important source of genomic instability in malignant diseases. Generally, the formation of a new constriction allows mitotic rescue of acentric chromosomes, preventing their loss. An increase in genomic alterations in tumor cells predicts a more aggressive disease course and adverse outcomes. Due to limited data, the prognostic significance of neocentromeres remains unclear. Further rigorous investigation is required to deepen our understanding of the mechanisms underlying neocentromere formation and their implications in cancer.

Constitutional mismatch repair deficiency (CMMRD) is a rare hereditary cancer predisposition syndrome that frequently manifests with pediatric high-grade gliomas. However, recognition remains challenging, particularly in the absence of a clear family history. We report a pediatric high-grade glioma with PMS2 deficiency and complex molecular alterations to highlight key diagnostic clues and the importance of routine mismatch repair assessment.