Emerging evidence suggests that viral integration into non-coding and genomically vulnerable regions may represent one of several mechanisms contributing to oncogenesis, warranting further investigation through long-read whole-genome sequencing (WGS).

Olaparib has demonstrated clinical benefit in patients with metastatic castration-resistant prostate cancer (mCRPC) harboring BRCA pathogenic or likely pathogenic variants (PVs) in randomized clinical trials; however, multicenter real-world data in Japanese patients remain limited.

TRIB3 is upregulated in non-small cell lung cancer (NSCLC) and associates with worse survival, yet targeted therapeutics remain lacking. Calcium phosphate (CaP) nanoparticles offer biocompatible, serum-stable delivery for siRNA therapy. Here, we developed CaP nanoparticles loading siRNA targeting TRIB3 (NPCaP/siTrib3) and evaluated antitumor efficacy and mechanisms in vitro and in vivo.

Polybromo-1 (PBRM1) modulates chromatin accessibility and transcription via six bromodomains that bind acetyl-lysine residues on nuclear proteins. PBRM1 variants exist in ~40% of clear cell renal cell carcinoma (ccRCC) cases. PBRM1 loss correlates with improved responses to antiangiogenics and immune checkpoint blockade, which are the standard of care for ccRCC therapy. Missense variants cluster within PBRM1 bromodomains and are present in 16% of ccRCC cases, with unknown impacts on therapeutic response. Since in-depth biophysical and cellular testing of the hundreds of PBRM1 missense variants reported in ccRCC and other cancer types is intractable, computational approaches can provide actionable variant impact assessments. We employed an integrated structural genomics analysis at the levels of protein sequence (2D), structure (3D), and molecular dynamics (4D) to evaluate the effects of all reported ccRCC-associated missense variants in the second and fourth bromodomains of PBRM1 (33 total) on molecular fitness (i.e., stability, structural integrity, and ligand binding). We also evaluated the concordance between molecular fitness and biophysical parameters of variant structural integrity (differential scanning fluorimetry, circular dichroism, and 1H-NMR spectroscopy) and ligand binding (AlphaScreen and electrophoretic mobility shift assays). Integrated molecular fitness scores correlated with measures of acetylated histone binding, while 3D and integrated molecular fitness scores correlated with measures of thermal stability. This integrated structural genomics analysis accelerates mechanistic understanding of how ccRCC missense variants impact PBRM1 bromodomain structure and function. This knowledge supports future studies correlating specific missense variants with PBRM1 tumor-suppressive functions and patient responses to antiangiogenics and immune checkpoint blockade to inform ccRCC personalized medicine approaches.

Triple negative breast cancer (TNBC) and ovarian cancer share many molecular features and are primarily treated with surgical resection and aggressive chemotherapy regimens. Unfortunately, survival rates for patients with advanced metastatic disease are poor, highlighting the need for innovative therapeutic approaches.

Recent advances in molecular and immunologic profiling have substantially refined the understanding of mycosis fungoides (MF) and Sézary syndrome (SS), the two most prominent subtypes of cutaneous T-cell lymphomas (CTCL). CTCL comprise a heterogeneous group of lymphoid malignancies characterized by clonal proliferation of malignant T-cell with cutaneous tropism. The pathogenesis of MF and SS appears to be driven by convergent oncogenic programs involving dysregulated JAK/STAT, NF-κB, PI3K/AKT/mTOR, and MAPK signaling, epigenetic reprogramming, apoptosis resistance, immune escape, and microenvironmental support. In parallel, altered surface phenotypes and chemokine receptor programs shape tissue tropism across skin, blood, and lymph nodes, while the tumor microenvironment promotes tumor persistence and Th2-skewed immune polarization. These insights have translated into novel targeted and immune-based therapies. This review summarizes current insights into the cell-intrinsic and microenvironmental biology of MF and SS and discusses emerging approaches aimed at achieving more durable and personalized disease control.

B-cell acute lymphoblastic leukemia (B-ALL) is the most common malignancy occurring in children and a leading cause of cancer-related mortality, thus there is an urgent need for development of novel therapeutic strategies for high risk B-ALL patients. The significance of IKZF1 gene alterations in B-ALL cases is controversial, as some studies have shown those to be associated with poor prognosis, while others have reported that deletion of exons 4-7 of the IKZF1 gene, which results in generation of IKAROS isoform 6, is related favorable prognosis. For the present study, clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 was employed for knockout of the IKZF1 gene and various IKAROS knockout lines were established, which allowed for investigation of precise functions of the gene by comparing four lines with different IKAROS isoform 1 and 6 statuses. The results clearly showed induction of significant differentiation and cell cycle progression in IKAROS isoform 6 knockout clones. Furthermore, knockout of IKAROS isoform 6 resulted in significant upregulation of the expression of IKAROS isoform 1 as well as signal transducer and activator of transcription 5 (STAT5) activity, which are considered to be related to the observed features. Further investigations are warranted to provide greater mechanistic insight regarding IKAROS-mediating pathways, which will lead to development of novel therapy for human B-ALL.

Immune checkpoint inhibitors (ICIs) have revolutionized lymphoma treatment, yet resistance driven by complex regulatory networks remains a major hurdle. Circular RNAs (circRNAs) have emerged as central signaling hubs that integrate metabolic, inflammatory, and oncogenic cues to fine-tune immune checkpoints such as PD-L1 and CD47 in lymphoma. Here, we systematically dissect the molecular mechanisms by which circRNAs govern immune checkpoints in lymphoma, including nuclear transcriptional control, interactions with RNA-binding proteins (RBPs), competitive endogenous RNA (ceRNA) networks, and micropeptide translation. We differentiate between cell-extrinsic, exosome-mediated reprogramming of the tumor microenvironment and cell-intrinsic circRNA circuits within lymphoma cells spatially. Subtype-specific investigations demonstrate the importance of Epstein-Barr virus (EBV)-encoded circRNAs in immune evasion and the synergistic interactions between 9p24.1 amplification and circRNAs in classical Hodgkin lymphoma (cHL). While therapeutic approaches including antisense oligonucleotides, CRISPR-Cas13, and nanodelivery technologies demonstrate preclinical synergy with ICIs, circulating circRNAs show potential as dynamic indicators for predicting ICI responses. We also critically examine ongoing discussions about the flaws of current model systems, the technological constraints of current validation techniques, and the physiological significance of the ceRNA hypothesis. Positioning circRNAs as multimodal regulatory hubs, this review provides a theoretical framework for developing circRNA-based immunotherapies to overcome resistance in lymphoma.

Nucleolar Protein 14 (NOP14), a highly conserved factor in eukaryotes, is essential for pre-18S rRNA processing and small ribosomal subunit assembly. Emerging evidence underscores its pivotal regulatory role in the progression of various malignancies. Nevertheless, its functional involvement in Diffuse large B-cell lymphoma (DLBCL), particularly its capacity to modulate the tumor immune microenvironment, remains to be fully elucidated.

EGFR exon 20 insertion (ex20ins) NSCLC typically shows limited response to immunotherapy. We report a rare case of a smoker with metastatic EGFR ex20ins (p.S768_D770dup) and high PD-L1 expression (TPS 50%) who achieved exceptional survival (OS = 63 months). Following progression on chemotherapy and intolerance to afatinib, the patient received paclitaxel plus tislelizumab. This combination yielded durable disease control. While the overall benefit of immune checkpoint inhibitors (ICIs) in EGFR-mutant NSCLC remains limited, this case suggests that chemo-immunotherapy (particularly taxane + PD-1 inhibition) may provide significant benefit in ex20ins tumors with high PD-L1 expression and smoking history. These findings highlight the critical value of targeted molecular profiling and offer a viable precision oncology strategy when novel targeted agents are inaccessible.

Coagulation and inflammation play crucial roles in the initiation and progression of cancer, and they exhibit a synergistic effect. However, a hematological biomarker and risk model based on coagulation and inflammatory have not yet been established in breast cancer.

High-grade gliomas cannot be fully understood without considering the biology of aging. In this study, we demonstrate that a set of genes previously established as predictors of tumor subtype and patient survival in gliomas can also be independently characterized as biomarkers associated with aging. Moreover, their expression changes during aging parallel with those seen in malignant transformation: genes which upregulation worsen prognosis are also upregulated with age. These findings support the hypothesis that glioma progression and aging share partially overlapping molecular mechanisms. We also demonstrate that while accelerated epigenetic and mitotic senescence - gauged by mathematical models (biological clocks) that track aging through specific changes in the DNA methylation of a set of CpG sites - appears inherent to various molecular variants of gliomas, its nature and prognostic significance vary depending on the specific subtype and the epigenetic clock model employed. Moreover, accelerated aging does not represent a universal hallmark of aggressiveness but rather a phenomenon specific to individual glioma subtype. In this paper, we provide a detailed discussion of the role of cellular senescence in glioma pathogenesis, with a particular focus on its key contribution to tumor growth control and therapeutic response. Additionally, we highlight the yet unresolved question of whether age-associated inflammation (inflammaging) acts as an independent driver of glioma progression or whether the tumor itself accelerates aging, and suggest the potential of profiling patients cellular aging in developing personalized treatment strategies.

Despite major advances in high-throughput genomics, proteomics, and multimodal imaging, a substantial gap persists between molecular tumor characterization and clinically actionable therapeutic decision-making, partly due to the limitations of conventional preclinical models in capturing tumor heterogeneity and predicting patient-specific drug response. Patient-derived organoids (PDO) have emerged as a promising platform to bridge this gap by enabling functional interrogation of individual tumors in a physiologically relevant three-dimensional context. PDO retain the genomic, transcriptomic, and histopathological features of their parental tumors while supporting long-term expansion, biobanking, and high-throughput pharmacological testing. In this review, we provide a clinically oriented overview of PDO technology as a key tool in functional precision oncology, summarizing current methodologies for tissue processing, organoid derivation, and quality control. We examine applications across multiple cancer types, including drug screening, radiotherapy response modeling, immuno-oncology co-culture systems, and CRISPR-based functional genomics, highlighting their role in directly measuring therapeutic vulnerability. We also integrate tumor-specific evidence across major malignancies, including colorectal, pancreatic, and breast cancers, where PDO-based pharmacotyping shows strong concordance with clinical outcomes and is increasingly incorporated into prospective trials. Finally, we discuss the integration of PDO with emerging technologies, including organoid-on-chip systems, artificial intelligence-driven analytics, and hospital-integrated workflows, as a critical innovation layer that is redefining their clinical applicability. These integrative approaches move PDO beyond static ex vivo models toward dynamic, and decision-support systems, with the potential to substantially enhance predictive accuracy and real-time therapeutic stratification. Collectively, these advances position PDOs as a promising component in next-generation precision oncology, supporting a transition from static genomics-based stratification toward dynamic, functionally guided therapeutic decision-making.

The Lung Cancer Compact Panel (cPANEL) is a recently approved highly sensitive multiplex gene panel in Japan that supports both DNA- and RNA-based next-generation sequencing. Although cytological specimens are acceptable for cPANEL, unfixed cell pellets or dedicated preservation tubes are typically recommended. However, evidence remains limited regarding whether residual liquid-based cytology (LBC) cell suspensions prepared for routine cytological diagnosis can be used directly for cPANEL testing without dedicated molecular preservation or additional preanalytical processing. In this study, we evaluated the feasibility of applying LBC specimens that are widely used in contemporary clinical practice to cPANEL.

Ferroptosis is a specific cell death form resulting from the iron-dependent lipid peroxidation, exhibiting an essential role in cancer progression. The purpose of this study was to explore the underlying mechanism of ferroptosis in lung cancer. The mRNA and protein expression levels were examined via real-time quantitative PCR and Western blotting. Cell malignant behaviors were assessed using cell counting kit-8 (CCK-8) assay, transwell assay, and flow cytometry. Ferroptosis was determined using the indicators lipid reactive oxygen species (ROS), glutathione (GSH), and Fe2+. Dual-luciferase reporter assay and chromatin immunoprecipitation assay were performed for binding analysis between activating transcription factor 4 (ATF4) and synthesis of cytochrome c oxidase 2 (SCO2). Associated proteins in mitogen-activated protein kinases (MAPK) signaling pathway were measured by Western blotting. A mouse model was established by implanting lung cancer cells for in vivo research. Lung cancer samples and cells exhibited high expression of SCO2. SCO2 downregulation restrained lung cancer cell growth by inducing ferroptosis. ATF4 was an up-regulated gene in lung cancer, and it elevated SCO2 expression by binding to the promoter of SCO2. ATF4 knockdown repressed cell proliferation and migration while facilitating apoptosis and ferroptosis by down-regulating SCO2. Inhibition of ATF4/SCO2 inactivated the MAPK signaling pathway. ATF4-mediated SCO2 promoted lung tumorigenesis in vivo. This study manifested that ATF4 controlled SCO2 to suppress ferroptosis by activating the MAPK pathway, thus contributing to lung cancer development.

Clear cell renal cell carcinoma (ccRCC) is the most prevalent subtype of kidney cancer and is frequently associated with poor clinical outcomes. Ribosome biogenesis, which is upregulated in many malignancies, plays a key role in tumor proliferation. Right open reading frame kinase 2 (RIOK2) is an atypical kinase essential for 40S ribosomal subunit maturation, but its role in ccRCC remains unexplored. We investigated the clinical and biological significance of RIOK2 in ccRCC. Immunohistochemical analysis of 166 ccRCC specimens revealed that high RIOK2 expression was significantly associated with advanced pathological stage, higher tumor grade, and shorter cancer-specific and progression-free survival. Public datasets confirmed the elevated RIOK2 mRNA expression in ccRCC, and its association with poor prognosis. Functional studies demonstrated that RIOK2 knockdown suppressed the proliferation, invasion, and migration of ccRCC cells. RNA sequencing, followed by gene set enrichment analysis, revealed that RIOK2 knockdown led to the downregulation of cell cycle-related pathways, including E2F targets. Analyses of public datasets further highlighted suppression of the G2/M checkpoint. Flow cytometry revealed G1 cell cycle arrest accompanied by reduced CDK2 protein expression in RIOK2-knockdown cells. Furthermore, the small-molecule RIOK2 inhibitor, NSC139021, suppressed ccRCC cell proliferation in a dose-dependent manner, with reduced efficiency in RIOK2-knockdown cells. Collectively, these findings identify RIOK2 as a clinically relevant factor associated with aggressive disease behavior and cell-cycle regulation in ccRCC.

Tumor-induced manipulations of myelomonocytic differentiation have been widely reported. Here, we describe the elicitation of a tumor-supportive cell type in a T lymphoma model in mice. We observed that the development of T lymphoma coincided with the appearance of a lymphoma-associated monocytic cell type (LAM) of host origin accompanied by a diminished dendritic cell (DC) population. RNA-sequencing and cytometric analyses revealed that LAMs shared markers with both DCs and with resident macrophages, most closely resembling monocyte-derived DCs (moDCs). The numbers of T lymphoma cells were negatively affected by reducing LAMs suggesting a helper function of LAMs for tumor growth. LAMs expressed Notch ligands, and treatments of lymphoma-carrying mice with Notch signaling-inhibitors LY3039478 and DAPT selectively decreased expansions of T lymphomas with or without Notch1 mutations, respectively. Mature LAMs did not proliferate in the periphery. Instead, their expansion resulted from altered myelomonocytic differentiation in the bone marrows of lymphoma-carrying mice with increases in common monocyte/DC precursors but with reduced granulocyte, monocyte and DC precursor populations. These data suggest that developing T lymphomas are capable of reprogramming monocyte/DC differentiation to increase the numbers of a tumor-promoting DC type, attract it to tumor locations and may engage in Notch ligand-dependent signaling to support lymphoma survival.

Despite major advances in radiation delivery, clinical outcomes remain constrained by tumor biology rather than technology. Conventional radiobiology has relied on reductionist two-dimensional (2D) systems that fail to capture the spatial, mechanical, and multicellular organization of tumors. Three-dimensional (3D) tumor models now resolve radiation response as a mechanobiological process coordinated across the extracellular matrix (ECM), adhesion signaling, cytoskeleton, and nucleus. This review focuses on a specific and we argue, underappreciated intersection: how 3D models expose integrin-mediated mechanotransduction as a determinant of the DNA damage response (DDR) and therapy resistance epitomized by cell adhesion-mediated radioresistance (CAM-RR) - an organizing principle we frame as the ECM-integrin-nucleus axis. We first delineate which model classes resolve which layer of this biology, distinguishing effects of three-dimensional organization from those of defined ECM-integrin signaling, and we treat the underlying mechanobiology quantitatively rather than descriptively. We then develop a mechanistic framework linking ECM architecture and stiffness to integrin-RTK crosstalk, cytoskeletal tension, LINC-mediated force transfer, and chromatin-dependent DNA repair, in which radiosensitivity emerges as a property of tissue context. From a translational standpoint, 3D models enable functional, radiation-specific assessment of context-dependent radiosensitivity and of mechanically targeted radiosensitization, while their integration with quantitative imaging and computational approaches further supports biomarker-guided and adaptive treatment strategies. We close with testable predictions that this framework generates, intended to guide the next phase of biology-driven radiation oncology.

Trophoblast cell surface antigen 2 (Trop-2) is a targetable transmembrane glycoprotein commonly overexpressed in breast cancer (BC). This study combines a systematic review and meta-analysis with a retrospective analysis of an independent early BC patient cohort, aiming to investigate the expression patterns of Trop-2 and their clinical significance in BC.

The tumour microenvironment (TME) influences breast cancer progression and treatment response. We investigated whether TME composition predicts tamoxifen benefit in postmenopausal women with oestrogen receptor-positive, HER2-negative (ER+HER2-) breast cancer.