Osteosarcoma (OS) is characterized by high metastatic potential and marked chemoresistance, with cancer stem cells (CSCs) serving as major drivers of malignant progression. Canine osteosarcoma (cOS) is considered an ideal comparative medicine model for human osteosarcoma (hOS). Accumulating evidence indicates that aberrant glucose metabolism and hexosamine biosynthetic pathway (HBP, hexosamine biosynthetic pathway)/O-linked N-acetylglucosamine (O-GlcNAc)ylation are involved in tumor progression; however, the precise mechanisms by which they regulate stemness in canine osteosarcoma cells remain unclear. In this study, we comprehensively employed glucose gradient culture, untargeted metabolomics, O-GlcNAc-modified proteomics, in vitro gene silencing, and a subcutaneous xenograft model in nude mice. Cellular functional assays revealed that high glucose significantly enhanced malignant phenotypes and stemness properties of canine osteosarcoma cells. Metabolomic analyses confirmed aberrant activation of the HBP in osteosarcoma cells. Further experiments demonstrated that high glucose enhances HBP flux and O-GlcNAcylation in a dose-dependent manner; silencing of glutamine-fructose-6-phosphate transaminase 1 (GFPT1), O-GlcNAc transferase (OGT), and O-GlcNAcase (OGA) verified that both the HBP pathway and O-GlcNAcylation positively regulate malignant biological behaviors and stemness maintenance. In vivo tumorigenesis assays demonstrated that OGT knockdown markedly suppressed osteosarcoma growth. O-GlcNAc-modified proteomics identified transducin-like enhancer of split 3 (TLE3), nuclear receptor corepressor 1 (NCOR1), and neurogenic locus notch homolog protein 2 (NOTCH2) as key differentially modified proteins, predominantly enriched in the Wingless/Integrated (Wnt) and Notch signaling pathways. Collectively, our findings demonstrate that high glucose activates the HBP pathway, elevates global O-GlcNAcylation levels, and modifies TLE3/NCOR1/NOTCH2, thereby promoting stemness maintenance in canine osteosarcoma stem cells. This study provides novel metabolic targets for precision therapy of osteosarcoma.

Cervical cancer remains a major global health challenge and a leading cause of gynecological cancer-related mortality, particularly in developing countries. Although persistent human papillomavirus infection is the primary driver of cervical carcinogenesis, host factors such as immune dysregulation and microbiome dysbiosis may contribute to disease progression. Corisin is a microbiota-derived peptide implicated in epithelial injury and fibrosis, but its role in cervical neoplasia is unknown. To investigate its potential involvement, circulating corisin levels were measured in 27 women with cervical intraepithelial neoplasia (CIN) or cervical cancer and compared with those in 15 healthy women. Corisin localization in cervical carcinoma tissues was examined by immunohistochemistry, and its biological effects were evaluated in HeLa cells. Circulating corisin levels were significantly elevated in patients with CIN and cervical cancer, with the highest levels observed in CIN3 and cervical squamous cell carcinoma. Corisin was detected within cervical carcinoma tissues in intracellular and extracellular compartments adjacent to tumor cells. In HeLa cells, corisin accumulated in mitochondria, impaired cell-cycle progression, induced apoptosis, increased p21 expression, and promoted epithelial-mesenchymal transition-like morphological changes. These findings suggest that corisin is elevated from the early stages of cervical neoplasia, is present within the cervical tumor microenvironment, and may contribute to pathogenic cellular processes associated with cervical cancer progression.

Hepatocellular carcinoma (HCC) arises predominantly in chronic liver disease with a uniquely tolerogenic microenvironment. Immune checkpoint inhibitors (ICIs) have improved the prognosis of advanced HCC, yet most patients exhibit low response rates or therapeutic resistance due to the highly immunosuppressive tumor microenvironment. Metabolic reprogramming is not only a core hallmark of HCC but also a key regulatory axis connecting tumor cells and the immune system. HCC cells exhibit pronounced Warburg glycolysis, upregulated glutaminolysis, aberrant lipid storage and oxidation, enhanced ketone metabolism, and altered polyamine flux. These metabolic alterations lead to nutrient competition, lactate accumulation, amino acid depletion, and oncometabolite signaling, resulting in T cell exhaustion, macrophage polarization, T cell expansion, and impaired dendritic cell function, thereby influencing tumor progression, immune escape, and therapeutic resistance. Targeting metabolic-immune crosstalk represents a promising strategy for reversing immunosuppression and enhancing the efficacy of immunotherapy. In this review, we systematically summarize the core patterns of metabolic reprogramming in HCC, dissect the molecular mechanisms of metabolic crosstalk at the tumor-immune interface, and discuss the role of immunometabolic remodeling in therapeutic resistance. This review aims to provide a comprehensive theoretical basis and new research directions for improving the efficacy of HCC treatment by targeting the metabolic-immune regulatory axis.

Glioblastoma (GBM) remains one of the most therapy-resistant human malignancies, yet the physiological limits of mitochondrial stress adaptation against which its remarkable resilience might be interpreted remain poorly defined. This opinion article proposes the developmental stress boundary framework, a hypothesis-generating model in which insect embryonic cells, particularly those of Drosophila melanogaster, serve as an experimentally tractable, non-malignant reference platform for quantitative mapping of mitochondrial stress tolerance. Within this framework, GBM stress tolerance may be interpreted not as the product of fundamentally novel adaptive mechanisms, but as a pathological displacement and long-term stabilization of conserved mitochondrial programs transiently engaged during normal embryonic development. The framework is intended to complement, rather than replace, existing models of glioblastoma biology. The proposed framework integrates four interconnected dimensions of mitochondrial adaptation-redox homeostasis, lipid metabolism and ferroptosis-like resistance, proteostasis, and metabolic flexibility-into a multidimensional physiological stress boundary that defines the limits of reversible cellular adaptation. Comparative evidence from developmental biology and glioblastoma research is consistent with the possibility that malignant cells expand these conserved adaptive programs beyond their normal physiological constraints, although this relationship has not yet been directly tested. The framework generates four testable predictions: (i) stress-response curves in GBM may be right-shifted relative to embryonic baselines while preserving their overall architecture; (ii) mesenchymal-like GBM states may exhibit the greatest displacement of stress tolerance; (iii) effective therapeutic strategies may require simultaneous compression of multiple adaptive dimensions to prevent compensatory responses; and (iv) pharmacodynamic biomarkers, including lipid peroxidation products and GSSG/GSH ratios, could provide early indicators of declining stress-buffering capacity during treatment. Establishing quantitative developmental baselines using insect embryonic systems, alongside complementary reference points such as tissue regeneration, may provide a conceptual and experimental basis for interpreting mitochondrial stress adaptation in glioblastoma. Rather than proposing a new explanatory model of glioblastoma biology, this framework seeks to provide a quantitative developmental reference against which mitochondrial stress adaptation in glioblastoma can be experimentally interpreted, tested, and, where necessary, revised.

Hepatocellular carcinoma (HCC) remains one of the most aggressive and lethal malignancies worldwide, with high rates of metastasis and recurrence contributing to its poor prognosis. There is an urgent need to elucidate the molecular mechanisms driving HCC progression and to develop effective therapeutic strategies. Metabolic reprogramming, especially aerobic glycolysis known as the Warburg effect, is a well-established hallmark of cancer. Concurrently, cancer stem cells (CSCs) play crucial roles in tumor initiation, therapy resistance, and recurrence. However, the involvement of long non-coding RNAs (lncRNAs) in linking metabolic alterations and stemness remains poorly understood. In this investigation, we identified LINC02041 as a significantly upregulated lncRNA in HCC tissues and demonstrated its oncogenic role in promoting cell proliferation. We found that STAT3 transcriptionally activates LINC02041 expression. Mechanistically, LINC02041 enhances the stability of SRSF1 protein by suppressing its ubiquitin-mediated degradation, thereby facilitating HCC cell proliferation, migration, glycolytic metabolism, and acquisition of stem-like properties. Our findings delineate a novel STAT3/LINC02041/SRSF1 regulatory axis that coordinately modulates glycolytic reprogramming and stemness maintenance in hepatocarcinogenesis. This study not only advances our understanding of HCC pathophysiology but also identifies LINC02041 as a promising prognostic biomarker and a compelling therapeutic target for novel therapeutic strategies against this aggressive malignancy.

Chordoma is a rare notochordal malignancy of the axial skeleton, and distant cutaneous metastasis is among its rarest manifestations-an under-recognised mimic of benign and malignant skin tumours that often presents with an incomplete clinical history.

Breast cancer (BC) is the most incidental cancer in women. Patients' living conditions and survival rates have significantly improved with the success of two first-line endocrine therapies of selective estrogen-receptor modulators (SERMs from 1977) and aromatase inhibitors (AIs from 1995). Unfortunately, both therapies have produced significant resistance. AI resistance reaches 50% in metastatic estrogen-dependent BC cases, leading oncologists to seek a substitute for current therapies. We target the reductive 17β-hydroxysteroid dehydrogenase type 7 (17β-HSD7), which stimulates the synthesis of the active estrogen estradiol (E2) and reduces the potent androgen dihydrotestosterone (DHT) simultaneously, triggering negative feedback on 17β-HSD7 expression. INH7(464), an improved 17β-HSD7 inhibitor, efficiently blocks estrogen conversion at an IC50 of 92 ± 8 nM. INH7(464) inhibited cell proliferation by decreasing E2 levels and restoring DHT, successively arresting the cell cycle in G0/G1 phase. In vivo, INH7(464) reduced tumor size by 49% on Day 22 in BC xenografts with T47D. INH7(464) reduced E2 levels in mouse blood circulation and xenograft tumor tissue. There is no demonstrated cytotoxicity or cardiotoxicity of INH7(464) on cellular levels and mouse models under the experimental conditions. 17β-HSD7 is a potential target for estrogen-dependent BC therapy, while INH7(464) is promising for a preclinical lead compound (PCT/CA2022/050966).

Hypoxia-driven regulatory mechanisms play a critical role in tumor progression and therapeutic resistance in hepatocellular carcinoma (HCC), yet hypoxia-responsive microRNAs (HRMs) remain incompletely characterized. This study aimed to identify HRMs in canine HCC to evaluate their diagnostic potential and translational relevance to human disease. Next-generation sequencing of two canine HCC cell lines under normoxic and hypoxic conditions identified 332 and 321 differentially expressed miRNAs, respectively. Integrating these with tumor tissue data revealed 11 HRMs, featuring consistent upregulation of cfa-miR-210 and cfa-miR-34a, which was validated via RT-qPCR in hypoxic cells and clinical tissues. Both miRNAs were significantly elevated in plasma-derived extracellular vesicles (EVs), highlighting their value as promising circulating biomarkers (AUC 1.00 for miR-210; 0.98 for miR-34a). Target gene and pathway analyses identified shared regulatory nodes, including TGIF2 and SPRED1; and enrichment of MAPK, Ras, PI3K-Akt, and Rap1 signaling, broadly linked to hypoxia adaptation, cellular metabolism, and stress-response signaling. Cross-species comparison with human HCC datasets showed that, while miR-210 associates with poor prognosis in human HCC, miR-34a exhibits tumor-suppressive features. These findings define complementary HRM programs in canine HCC, reflecting conserved adaptive and stress-limiting regulatory mechanisms with potential diagnostic and translational relevance to human HCC.

Lymphomas are a heterogeneous group of aggressive lymphoid malignancies characterized by frequent extranodal involvement. Musculoskeletal manifestations, although uncommon, represent a clinically significant and under-recognized presentation that often mimics primary bone tumors, soft tissue sarcomas, and infectious conditions, leading to diagnostic delays and inappropriate initial management. This narrative review synthesizes current evidence on the clinical presentation, imaging characteristics, pathology, and biological basis of musculoskeletal T-cell lymphomas, with particular emphasis on implications for orthopedic practice. A structured literature search was conducted across major databases from 2000 to the present, and evidence was integrated across clinical, radiologic, pathologic, and therapeutic domains. Musculoskeletal involvement most commonly presents with localized bone pain, soft tissue masses, or pathological fractures, with imaging features such as diffuse marrow infiltration, soft tissue extension, and relatively preserved cortical bone serving as important diagnostic clues. Definitive diagnosis relies on tissue biopsy with comprehensive immunophenotypic and molecular characterization. Emerging insights into the tumor microenvironment highlight its role in disease progression and therapeutic response, offering potential avenues for targeted treatment strategies. Management is subtype-specific and centers on systemic therapy, with selective roles for radiotherapy and orthopedic intervention in cases of structural compromise. Early recognition through integrated clinical, imaging, and pathological assessment, combined with multidisciplinary collaboration, is essential to optimize outcomes in this rare but challenging disease entity.

Caspase-8 and the NF-κB essential modulator (NEMO, also referred to as IKKγ) play critical roles in controlling TNF-α-induced cell death and survival in hepatocytes. The aim of this study was to generate a hepatocyte-derived cell line in which the Casp8 and Nemo genes can be conditionally inactivated simultaneously to investigate the significance of the corresponding signaling pathways. To this end, we induced hepatocellular carcinoma in Casp8f/fNemof/f mice using diethylnitrosamine and established an immortalized hepatoma cell line from explanted liver tumors, which is subsequently referred to as ΔCN60. ΔCN60 cells still retain floxed Casp8 and Nemo alleles, allowing for efficient Cre-mediated deletion to generate Casp8ΔNemoΔ derivatives. Loss of both Caspase-8 and NEMO inhibits cell proliferation, increases the expression of tumor and progenitor markers (AFP, CD133), reduces albumin expression, and blocks TNF-α-induced NF-κB p65 nuclear translocation. ΔCN60 Casp8ΔNemoΔ cells display altered sensitivity to prolonged TNF-α exposure, suggesting a potential shift in necroptosis-associated signaling pathways, although necroptotic cell death was not directly demonstrated. ΔCN60 serves as a versatile hepatoma model for investigating Caspase-8/NEMO-dependent TNF-α signaling and hepatocyte plasticity and may help prioritize future in vivo experiments by enabling selected mechanistic questions to be addressed first in vitro.

Background: Recent evidence suggests that the antidepressant vortioxetine (Vx) inhibits the growth of glioblastoma (GBM), the most aggressive primary malignant tumor of the CNS. We used five patient-derived GBM cell lines to confirm the anti-GBM effect of Vx and explore its mechanism(s) of action. Methods: We performed in silico analysis, PCR, TUNEL assay, colony assay, and proliferation assay. Results: Vx potently inhibited GBM cell growth, and showed efficacy at concentrations of 0.1 μM that roughly correspond to therapeutic concentrations of Vx in major depression. Other antidepressants, i.e., fluoxetine and duloxetine, inhibited GBM cell growth only at high concentrations. Computational analysis showed that at least three receptor targets of Vx (5-HT7, 5-HT1D, and 5-HT1B) were expressed at moderate/high levels in GBM. The 5-HT1B receptor transcript was found in all GBM cell lines and was the only detectable Vx target in three of the five cell lines. Blocking 5-HT1B with SB224289 abolished the anti-GBM effect of Vx, even in cells expressing other Vx. Conclusions: These findings demonstrate that therapeutic concentrations of Vx inhibit GBM cell proliferation and suggest that this action may be mediated, at least in part, by 5-HT1B receptor activation.

Laryngeal cancer requires precise and minimally invasive therapeutic strategies to preserve critical physiological functions. Herein, an oxygen-embedded fused-ring organic semiconductor (COi8FIC) was reported, which is formulated into multifunctional nanoparticles for near-infrared (NIR)-triggered multimodal phototherapy. The incorporation of oxygen atoms into the conjugated backbone, together with fluorinated cyanoindanone end-groups, narrows the bandgap to 1.35 eV and enhances intramolecular charge transfer, thereby promoting non-radiative decay and intersystem crossing. As a result, COi8FIC nanoparticles exhibit a high photothermal conversion efficiency of 62% and generate multiple reactive oxygen species (•OH, O2-, and 1O2) via synergistic Type I and Type II photodynamic pathways. In vitro, the nanoparticles produce approximately 2.5-fold higher ROS levels than monotherapies. In vivo, NIR irradiation induces rapid hyperthermia (ΔT ca. 23.6 °C), resulting in a tumor growth inhibition rate of 93.3%. Tumor regression was observed in all treated mice, with complete tumor eradication in three of five mice and near-complete elimination in the remaining two, with no significant irreversible organ damage. These results highlight the potential of this system as a promising platform for multimodal phototherapy of laryngeal cancer.

Free radicals with reactive chemical properties can combat tumors without inducing drug resistance. Reactive oxygen species (ROS) have been widely applied in tumor therapy; however, the prevalent hypoxic conditions within tumors severely hinder the generation of ROS, leading to suboptimal antitumor efficacy. Herein, we designed an endogenous H2O2-triggered chlorine radical nanogenerator (Cl•) and hydroxyl radicals(•OH), which have better kinetic advantages and higher catalytic activity in catalyzing the H2O2 reaction. In vitro cytotoxicity tests revealed that the nano-urchins induced marked cancer cell death (up to ∼80% at the highest tested concentration) in a concentration-dependent manner, attributable to the chlorine radical-mediated oxidative stress. Moreover, the H2O2-specific activation strategy reduces toxic side effects on normal tissues, thereby enhancing the safety of tumor therapy. Finally, compared with conventional Cu2O nanocatalysts that solely generate •OH, our designed nano-urchins exhibit enhanced therapeutic efficacy, which is mainly attributed to the synergistic therapeutic effect. Therefore, our nano-urchins can serve as a novel nanocatalyst for tumor therapy.

SSEA3, SSEA4, and Globo H glycosphingolipids have been implicated in tumor progression and immune modulation across various malignancies. However, their clinical significance in extrahepatic cholangiocarcinoma (eCCA) remains largely undefined. This study aimed to evaluate the expression levels and prognostic relevance of SSEA3, SSEA4, and Globo H in patients with eCCA.

Hormone receptor-positive/Human epidermal growth factor receptor 2-negative (HR+/HER2-) early breast cancer accounts for the majority of breast cancer cases. Although chemotherapy can reduce recurrence risk, its use in HR+/HER2- high-risk disease remains complex in clinical practice. We aimed to examine regional variation in chemotherapy use in Sweden and its association with prognosis.

Distal pancreatectomy with celiac axis resection (DP-CAR) is an established procedure for the resection of celiac-trunk-infiltrating carcinomas of the pancreatic corpus or cauda. In contrast, total pancreatectomy with celiac axis resection (TP-CAR) remains a controversial procedure, which is sporadically mentioned in the literature. This study aimed to compare perioperative and survival outcomes following TP-CAR with those of the established DP-CAR operation.

Laslo et al. recently reported a guided denoising diffusion implicit model for spatial tumor growth prediction on magnetic resonance imaging (MRI) in pediatric diffuse midline glioma. Their proof-of-principle study demonstrates the feasibility of generative artificial intelligence (AI) for producing patient-specific tumor growth maps as an early step toward informing personalized radiotherapy planning in data-limited pediatric neuro-oncology settings. However, the external validation cohort comprised only 13 patients, and growth-region prediction performance, measured using the continuous Dice coefficient (cDICE; median ≈ 0.22; range 0.071-0.376), was considerably weaker than full-tumor performance (cDICE median ≈ 0.81; range 0.439-0.877). In this Matters Arising, we provide a focused methodological commentary on several issues that should be considered when interpreting the translational implications of this work.

Metastasis remains the principal cause of cancer mortality, with the lungs representing one of the most frequent and clinically challenging sites. The tumor microenvironment, particularly tumor-associated macrophages (TAMs), plays a pivotal role in establishing and maintaining metastatic niches. Yet, how host ketone bodies influence the immune microenvironment to govern metastatic progression is poorly defined.

Nuclear receptor coactivator 3 (NCOA3) is associated with various cancers, but its function and mechanism in glioblastoma multiforme (GBM) are still unclear. Bioinformatics analysis, in vitro cell experiments (NCOA3 silencing (si-NCOA3) or NCOA3 small-molecule inhibitor SI-2), in vivo animal models, and metabolic level detection were used to elucidate the activity of NCOA3 in GBM. The data revealed that GBM tissues had NCOA3 overexpression, which was linked with poor prognosis. It regulates pathways related to glycolysis, the cell cycle, and immunosuppression. Functionally, si-NCOA3/SI-2 suppressed GBM cell proliferation and migration. In vivo, sh-NCOA3/SI-2 demonstrated anti-glioma effects. Metabolically, treatment with si-NCOA3/SI-2 reduced glucose uptake, pyruvate and lactate production, ATP levels, and glycolysis-related enzyme expression in GBM cells. Combination therapy with SI-2 and TMZ enhanced GBM cell sensitivity to TMZ. Single-cell RNA sequencing revealed high NCOA3 expression in glioma stem cells (GSCs). si-NCOA3 inhibited GSCs proliferation and self-renewal while reducing the expression of Nestin and SOX2. NCOA3 is an oncogene in GBM. In mechanism, NCOA3 promotes GBM progression by enhancing the Warburg effect. In addition, NCOA3 is also highly expressed in GSCs and significantly promotes their proliferation and self-renewal ability. NCOA3 may represent a promising therapeutic target for GBM.

Cutaneous T-cell lymphoma (CTCL) and classic Hodgkin lymphoma (cHL) are distinct lymphoid neoplasms with differing cells of origin and immunophenotypes. Morphological overlap between these entities can pose significant diagnostic challenges, particularly in patients with a concurrent or prior lymphoma diagnosis.