Neural precursor cell expressed developmentally down-regulated 4 (NEDD4) has been implicated in the progression of various human malignancies, including hepatocellular carcinoma (HCC). However, the relationship between NEDD4's ubiquitin ligase activity and the motility of HCC cells remains unclear. We investigated the significance of the NEDD4/EPHB6 (erythropoietin-producing hepatocyte B6) axis in driving epithelial-mesenchymal transition (EMT) progression in HCC. In this study, we investigated the role of the HECT-type E3 ubiquitin ligase NEDD4 in HCC progression and identified its downstream substrate through integrated bioinformatic screening, protein-level validation, and NEDD4 immunoprecipitation coupled with mass spectrometry. The regulatory relationship between NEDD4 and EPHB6 was examined using ubiquitination assays, protein stability analysis, and functional rescue experiments. Potential downstream signaling changes associated with the NEDD4-EPHB6 axis were further examined through pathway analysis and molecular validation. NEDD4 silencing suppressed, whereas its overexpression enhanced HCC cell invasion and migration. Mechanistically, NEDD4 functioned as an E3 ubiquitin ligase that promoted Lys48-linked polyubiquitination and proteasomal degradation of erythropoietin-producing hepatocyte B6 (EPHB6), resulting in reduced EPHB6 protein abundance without altering EPHB6 mRNA levels. Disruption of the NEDD4-EPHB6 axis attenuated EMT, which was further validated in a xenograft mouse model. Moreover, NEDD4 protein expression was inversely correlated with EPHB6 levels in clinical HCC tissues. In summary, our study identifies the NEDD4-EPHB6 axis as a previously unrecognized regulator of EMT-associated malignant progression in HCC and demonstrates its association with activation of TGF-β/SMAD2/3 signaling. This study provides new mechanistic insight into how post-translational regulation of membrane-associated proteins controls HCC progression.

Bispecific antibodies (BsAbs) have shown marked efficacy in relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL). However, their clinical utility is constrained by cytokine release syndrome (CRS). Therefore, identification of strategies to mitigate CRS without compromising the antitumor activity of BsAbs is important. This study aimed to investigate the characteristics of CRS in BsAb therapies and identify effective intervention approaches. Analysis of serum cytokine profiles from patients receiving BsAbs revealed that IL-6, IL-8, and IL-10 levels were markedly elevated at CRS onset. Our results, together with public data, suggested that monocytes/macrophages served as the primary sources of these cytokines. In vitro experiments confirmed that the presence of macrophages substantially enhanced BsAb-induced cytokine production. In vivo macrophage depletion attenuates CRS-related cytokine release, underscoring the central role of macrophages in BsAb-induced CRS. Furthermore, in vitro experiments and in vivo humanized models have shown that bruton's tyrosine kinase (BTK) inhibitors modulate macrophage phenotype and reduce the production of IL-6, IL-8, and IL-10 without impairing the therapeutic efficacy of BsAbs. Collectively, BTK inhibitors can reduce key cytokine production in CRS by regulating the phenotype of BsAb activated macrophages, potentially lowering CRS risk and severity during BsAb therapy.

Platelets play a crucial role in regulating tumor progression, but the mechanisms underlying platelet-induced metabolic reprogramming in hepatocellular carcinoma (HCC) remain incompletely understood. Here, metabolomic profiling identified significant accumulation of leucine in HCC cells following platelet incubation. Co-culture with platelets promoted HCC cell proliferation, migration, and invasion in complete medium, whereas leucine deprivation in the co-culture medium attenuated these malignant behaviors. Mechanistically, platelets selectively stimulated the phosphorylation of S6K1 and downstream S6, an activation that was suppressed under leucine-deficient conditions. In addition, pharmacological inhibition of S6K1 activity using PF-4708671 reduced platelet-promoted cellular proliferation, migration, and invasion, confirming the S6K1/S6 axis as an essential functional effector of this response. In vivo, dietary leucine restriction reduced tumor growth following platelet pre-incubation in the MHCC-97H xenograft model. Together, these findings demonstrate that leucine accumulation and subsequent S6K1/S6 activation mediate platelet-promoted HCC progression, indicating that targeting leucine availability or S6K1 signaling may offer therapeutic strategies for platelet-associated HCC.

In March 2025, the Japanese Society for Hereditary Tumors and the Ministry of Health, Labour and Welfare (MHLW) Research on Promotion of Cancer Control Program Grant Number JPMH 23EA1037 published the "Japanese Society for Hereditary Tumors Guidance: Hereditary Cancer Syndromes with Multigene Panel Testing (MGPT), 2025 Edition." Unlike conventional phenotype-based guidelines, this guidance promotes preemptive cancer medicine based on genotype. The guidance establishes standardized criteria for MGPT eligibility, emphasizing its utility in both cancer-affected and cancer-free individuals to identify actionable germline pathogenic variants (GPVs). Key recommendations include the integration of gene-specific curation for variant interpretation and the implementation of structured clinical practice systems for risk management. By providing evidence-based management strategies for 56 cancer-susceptibility genes, this guidance facilitates the shift toward genotype-driven oncology. This digest assists healthcare providers in utilizing MGPT and supports shared decision-making for patients and their relatives.

Cervical cancer seriously threatens women's life and health, highlighting the urgent need for targeted therapies. TP53-induced glycolysis regulatory phosphatase (TIGAR), upregulated in cervical cancer and regulated by HPV E6, may be involved in cervical cancer progression, making its inhibition a potential therapeutic strategy. This study aims to investigate the role and mechanism of TIGAR in cervical cancer ferroptosis resistance and identify a TIGAR-targeting drug to suppress cervical cancer advancement. Through RNA-seq, transmission electron microscopy, and western blotting, we found that TIGAR knockdown significantly promoted ferroptosis by increasing intracellular lipid reactive oxygen species (ROS) levels. Furthermore, through molecular docking, CETSA, and SPR analysis, we identified Dioscin as a compound that binds to TIGAR. Dioscin treatment effectively inhibited cervical tumors via TIGAR both in vitro and in vivo. Mechanistically, Dioscin interacted with TIGAR and promoted ferroptosis, at least in part, through the TIGAR-ROS axis. Collectively, these findings indicate that TIGAR suppresses ferroptosis via lipid ROS reduction, while Dioscin counteracts this process, at least in part, through the TIGAR-ROS axis. Thus, Dioscin holds promise as a potential targeted therapeutic agent for cervical cancer.

Deruxtecan-based antibody-drug conjugates (DXd ADCs) provide substantial clinical benefit across multiple malignancies but are associated with clinically significant interstitial lung disease (ILD), for which the underlying mechanisms remain incompletely understood. To enable mechanistic and translational studies, we established a transgenic rat model expressing human trophoblast cell-surface antigen 2 (hTROP2) under the control of the surfactant protein C promoter, driving selective expression in alveolar type II (AT2) cells. Repeated administration of a TROP2-directed DXd ADC with an average drug-to-antibody ratio of 7.9 (TROP2-DXd) reproducibly induced lung injury characterized by alveolar epithelial damage, inflammatory cell infiltration, and fibroblast/myofibroblast proliferation. These pathological changes were accompanied by inflammatory and tissue-remodeling transcriptomic responses, including increased expression of fibrosis-associated genes and decreased expression of AT2-associated genes. These molecular alterations showed partial concordance with molecular programs observed in a cynomolgus monkey ILD model. In hTROP2 transgenic rats, prednisolone markedly attenuated TROP2-DXd-related lung injury and inflammatory and tissue-remodeling transcriptomic responses without altering systemic exposure. Although hTROP2 expression is transgene-driven and does not fully recapitulate physiological expression patterns and distribution in normal human lungs, this model provides a controlled experimental system for evaluating epithelial injury-associated mechanisms. Notably, parallel studies in BALB/c and C57BL/6 mice showed no pulmonary findings despite prolonged high-exposure dosing, suggesting species-dependent susceptibility. Collectively, this transgenic rat model represents a unique rodent ILD model that recapitulates key pathological and molecular features and provides a scalable, experimentally tractable platform for mechanistic and translational evaluation across DXd ADCs.

Lysine-specific demethylase 1 (LSD1/KDM1A) is a potential therapeutic target in non-seminomatous testicular germ cell tumors (NSGCTs). We assessed LSD1 and Ki-67 immunostaining in 74 histologically distinct tumor components from 53 patients with testicular germ cell tumors and studied the selective LSD1 inhibitor NCL1 in embryonal carcinoma models. LSD1 positivity was higher in pooled non-seminomatous than seminomatous components (p = 0.0104). Following Bonferroni correction, teratoma and yolk sac tumor components showed higher LSD1 positivity than seminoma, whereas the embryonal carcinoma-seminoma comparison did not reach statistical significance (adjusted p = 0.08). LSD1 positivity correlated with Ki-67 positivity. In embryonal carcinoma cells, NCL1 increased H3K9me2 enrichment at SOX2 and OCT4 promoter regions, decreased pluripotency-associated proteins and survivin, and increased cleaved caspase-3 and apoptotic cell populations while reducing cell viability. NCL1 also reduced viability in cisplatin-adapted cells and further reduced viability when combined with cisplatin in parental cells. In vivo, treatment initiated before tumors became measurable suppressed subsequent xenograft outgrowth, whereas treatment of established xenografts did not significantly inhibit growth at the doses tested. Together, the histological findings and responses observed in embryonal carcinoma models support LSD1 as a potential therapeutic target for further investigation in NSGCT; NCL1 efficacy in other histological subtypes and against established tumors remains to be established.

Conventional surveillance tools for hepatocellular carcinoma (HCC) have limited sensitivity. Circulating cell-free DNA (cfDNA)-based liquid biopsy is a promising minimally invasive approach; however, its overall diagnostic performance remains unclear. This meta-analysis aimed to comprehensively evaluate the diagnostic accuracy of cfDNA-based liquid biopsy in HCC. Following PRISMA-DTA guidelines, we searched PubMed, EMBASE, and Web of Science until July 2026. Diagnostic accuracy data were pooled using bivariate random-effects models. Methodological quality was assessed using QUADAS-2 and NOS. A total of 29 studies (4250 HCC patients, 7982 controls) were included. Pooled sensitivity and specificity of cfDNA-based testing were 0.82 (95% CI: 0.76-0.86) and 0.91 (95% CI: 0.88-0.93). The area under the summary receiver operating characteristic curve (AUC) was 0.93 (95% CI: 0.91-0.96). Subgroup analyses showed higher sensitivity in advanced HCC 0.91 (95% CI: 0.85-0.95) than early HCC 0.77 (95% CI: 0.71-0.83). Methylation profiling yielded relatively higher sensitivity 0.84 (95% CI: 0.77-0.89), whereas fragmentomics showed relatively favorable specificity 0.93 (95% CI: 0.88-0.96). Combining cfDNA-based testing with alpha-fetoprotein (AFP) significantly improved sensitivity compared with cfDNA alone (0.78 vs. 0.65). No significant publication bias was detected (p = 0.83). cfDNA-based liquid biopsy achieves high diagnostic accuracy for HCC. As exploratory observations, methylation-based assays with relatively higher sensitivity may have potential value for screening high-risk populations, while fragmentomics-based assays with relatively favorable specificity may aid differential diagnosis. Combining cfDNA-based liquid biopsy with AFP further improves diagnostic performance, supporting cfDNA as a promising noninvasive tool for HCC detection. Trial Registration: This systematic review was registered on PROSPERO: CRD420261293877 (https://www.crd.york.ac.uk/PROSPERO/).

Immunotherapy enhances antitumor immunity to eliminate malignant cells and has great potential to prevent tumor recurrence and distant metastasis. In addition to direct tumor destruction, microwave ablation (MWA) remodels the tumor immune microenvironment (TIME) and induces antitumor immune responses, providing a strong rationale for combination with immunotherapy. As key regulators of immune-cell trafficking and function, chemokines critically mediate the synergy between MWA and immunotherapy. In this review, we summarize the effects of MWA on the TIME, the central role of chemokine networks in this process, and recent advances in MWA-based combinatorial immunotherapy, including clinical progress. We also discuss current challenges and future directions to support the optimization of multimodal cancer therapy and improve clinical outcomes.

BRAF alterations occur across diverse gliomas and glioneuronal tumors, but their alteration-specific clinicogenomic contexts in real-world cancer genomic profiling cohorts remain incompletely characterized. We analyzed BRAF-altered brain tumors registered in the Japanese Center for Cancer Genomics and Advanced Therapeutics database from June 2019 to March 2026. Operational diagnostic harmonization was performed using available clinicopathological and genomic information. Grade-stratified analyses focused on BRAF p.V600E-positive gliomas and glioneuronal tumors. Among 413 BRAF-altered brain tumors, 344 were classified as gliomas and glioneuronal tumors after harmonization. Within this cohort, the major alteration contexts included BRAF p.V600E-positive tumors (n = 166), KIAA1549::BRAF fusion-positive tumors (n = 60), amplification-only tumors (n = 15), and tumors with other BRAF alterations (n = 109), with overlap in a subset. KIAA1549::BRAF fusion-positive tumors were mainly associated with low-grade glioma contexts, particularly pilocytic astrocytoma. Amplification-only tumors showed marked enrichment of MET alterations, all representing MET amplification, together with frequent EGFR and TP53 co-alterations, supporting a receptor tyrosine kinase-amplified, copy-number-rich context. Among 118 grade-evaluable BRAF p.V600E-positive gliomas and glioneuronal tumors, CDKN2A/B homozygous deletion and TP53/ATRX alterations were enriched in higher-grade groups, and high-grade tumors showed increased tumor mutational burden, although hypermutator phenotypes were rare. BRAF alteration classes define distinct clinicogenomic contexts in gliomas and glioneuronal tumors. These findings highlight both the opportunities and methodological challenges of nationwide real-world cancer genomic profiling datasets in central nervous system tumor research.

Chimeric antigen receptor (CAR)-T cell therapy has transformed the treatment of hematologic malignancies and established a new paradigm for engineered cellular immunotherapy. However, its broader clinical application remains constrained by complex autologous manufacturing, high cost, limited scalability, variable product quality, suboptimal efficacy in solid tumors, and treatment-related toxicities. To address these challenges, recent advances in CAR-T cell therapy can be viewed across four interconnected dimensions: functional engineering, manufacturing innovation, alternative cell sources, and in vivo CAR programming. Functional engineering includes cytokine-armored, checkpoint-resistant, multi-targeting, and modular or switchable CAR platforms designed to enhance efficacy, persistence, and safety. In parallel, manufacturing innovations such as shortened culture protocols, automated closed systems, and preservation of less differentiated T-cell states aim to improve product potency while reducing production time and complexity. Alternative cell sources, including allogeneic donor-derived and induced pluripotent stem cell (iPSC)-derived platforms, may further enable standardized, scalable, and potentially off-the-shelf therapies. Finally, in vivo CAR programming has emerged as a fourth dimension in which endogenous immune cells are directly engineered within patients using viral or non-viral gene delivery systems. This review summarizes these interconnected advances and discusses how they may collectively shape the next generation of CAR-based immune therapies.

CDK4/6 inhibitors represent a key therapy for HR+/HER2- breast cancer, yet resistance and limited efficacy in triple-negative breast cancer (TNBC) remain significant challenges. Using a self-established drug combination prediction platform, we identified a strong synergy between the CDK4/6 inhibitor palbociclib and the natural compound curcumin across both HR+/HER2- and TNBC models, an effect that was also observed with ribociclib. Mechanistically, the combination led to a collapse of redox homeostasis. Despite upregulating transcriptional antioxidant responses, the treatment downregulated critical ROS-detoxifying enzymes (e.g., GPX4) and depleted glutathione. This imbalance induced lethal oxidative stress, lipid peroxidation, and extensive DNA damage. Furthermore, excessive ROS accumulation contributed to suppression of epithelial-mesenchymal transition (EMT) and reduced migratory and invasive phenotypes. The antioxidant N-acetylcysteine (NAC) attenuated both cytotoxicity and migration inhibition, supporting a central role for ROS in these effects. Together, these findings identify a redox-based mechanism underlying the combination and provide a rationale for further preclinical evaluation in HR+/HER2- breast cancer and TNBC.

Gastric cancer (GC) is a leading lethal malignancy globally. Gastric precancerous lesion (GPL) represents a critical step in GC, but its neural regulatory mechanisms remain largely unclear. We combined bioinformatics, patch-clamp recording, immunofluorescence, and chemogenetics to investigate serotonergic and cholinergic signaling in GPL. An N-methyl-N-nitrosourea (MNU) -induced mouse model was used for in vivo validation. High 5-HTR1D expression correlated with poor survival in gastric adenocarcinoma patients and was upregulated in AGS and MKN45 cells, as well as in gastric tissues of GPL mice. 5-HT evoked non-selective cation currents involving 5-HTR1D and TRPV4 in gastric epithelial and cancer cells, as supported by both pharmacological inhibition and siRNA-mediated TRPV4 knockdown. Blockade of 5-HTR1D or TRPV4 attenuated intestinal metaplasia and dysplasia, and this improvement was accompanied by reduced AKT/mTOR activation in GPL mice. Increased gastric M3R/5-HT co-localization was associated with elevated acetylcholine and overactivated cholinergic neurons in the dorsal motor nucleus of the vagus (DMV). Chemogenetic inhibition of DMV cholinergic neurons decreased ChAT and 5-HT levels and alleviated gastric pathology in GPL mice. These findings suggest that 5-HT/5-HTR1D signaling may promote TRPV4-involved cation currents, contributing to mucosal pathology and intestinal metaplasia in GPL model mice, whereas DMV cholinergic neurons projecting to the stomach may facilitate gastric 5-HT secretion and thereby potentially contribute to GPL progression. This work establishes a novel neuro-epithelial network linking vagal cholinergic output to serotonergic signaling that may be involved in GPL progression, providing potential targets for prevention and intervention.

Germline pathogenic/likely pathogenic (P/LP) variants inform cancer treatment and prevention, yet real-world detection patterns and downstream clinical management remain poorly characterized in East Asian hereditary cancer cohorts. This retrospective cohort study included 5829 patients with cancer who underwent germline testing at the National Cancer Center, Republic of Korea, between April 2006 and April 2023 using BRCA1/2-only testing or multigene panel testing. We examined P/LP variant prevalence, detection patterns under the revised national reimbursement criteria, gene group-stratified post-test clinical management, and variant reclassification outcomes. Among 5829 patients (96.6% female; median age, 51 years), 987 (16.9%) carried P/LP variants. Detection rates differed across reimbursement criteria, with the highest rates in patients with ovarian cancer (24.2%) and those meeting multiple criteria (up to 39.3%). Among P/LP carriers, 773 (78.3%) received at least one post-test clinical action; however, action rates differed substantially across gene groups, ranging from 84.3% among BRCA1/2 carriers to 46.0% among mismatch repair gene carriers. Of 1384 initial variants of uncertain significance, 25 (1.8%) were reclassified as P/LP, identifying 46 additional carriers. Overall variant frequencies were strongly shaped by the breast and ovarian cancer-predominant cohort composition, whereas documented post-test clinical actions varied across gene groups. Variant reclassification identified additional P/LP carriers, supporting the need for structured recontact and follow-up pathways.

t(11;14) (q13;q32) occurs in approximately 15%-25% of multiple myeloma (MM) cases and has traditionally been regarded as a standard cytogenetic risk factor. However, recent evidence suggests that MM with t(11;14) exhibits heterogeneous biological characteristics and clinical outcomes distinct from those associated with other cytogenetic risk categories. In a post hoc analysis of the prospective JSH-MM-15 study, we investigated the prognosis of newly diagnosed MM patients to identify prognostic features unique to t(11;14)-positive cases and to evaluate treatment factors influencing outcomes. Among 482 patients evaluated for t(11;14), 131 (27%) were positive. Overall survival (OS) in t(11;14)-positive patients was intermediate between standard- and high-risk groups, whereas progression-free survival (PFS) was comparable to that of high-risk cases. Deep response rates, including ≥ complete response (CR)/stringent CR and ≥ very good partial response, were lower in t(11;14)-positive MM than in other risk groups, and these responses were not associated with survival in t(11;14)-positive cases, in contrast to t(11;14)-negative MM. Compared with t(11;14)-negative MM, t(11;14)-positive patients more frequently expressed CD20 and less frequently expressed CD56 on myeloma cells. Exploratory analyses showed that, despite higher ≥ CR rates, OS was worse in patients with CD20-negative/CD56-negative tumors among t(11;14)-positive MM. Among CD20-positive patients, PI-containing regimens were associated with better OS, although no significant PFS benefit was observed. These findings support the biological and clinical heterogeneity of t(11;14)-positive MM and highlight the need for prospective validation of subgroup-specific treatment outcomes.