Tyrosine kinase inhibitors (TKIs) have markedly improved the prognosis of chronic myeloid leukemia (CML). In Japan, in addition to the four established first-line TKIs, asciminib is now approved as an initial therapy, expanding the treatment options. Nevertheless, more than 10% of patients treated with asciminib over 48 weeks, and approximately 20-30% of those receiving other TKIs over five years, require second-line therapy because of resistance or intolerance. As first-line choices diversify, selecting the optimal second-line regimen has become increasingly complex. For intolerance, switching should be guided by the adverse-event profile with attention to potential cross-intolerance. For resistance, assessment of BCR::ABL1 mutations is essential, and second-line agents should be chosen according to the initial TKI and mutation sensitivity. This article summarizes the criteria and timing for switching to second-line therapy and key considerations for selecting and managing second-line TKIs, and briefly reviews the evidence for asciminib and ponatinib in second-line and later settings.

Pancreatic ductal adenocarcinoma (PDAC) is highly aggressive with a high mortality rate. Intra-tumoral heterogeneity (ITH) increases the severity of PDAC and makes treatment difficult. Insights are provided on ITH to understand the diversity of microenvironment (ME) components, biomarkers, different subsets of tumor-associated cells, and immune cells, as well as metabolic reprogramming, autophagy, and apoptosis in PDAC. Single-cell RNA sequencing (scRNA-seq) is a sensitive technique that provides spatially resolved transcriptomic profiling. In this review, we discussed the sample preparation, library preparation, data analysis, and challenges associated with the technology. We have outlined a stepwise process workflow that utilizes computational approaches based on experimental requirements, supported by relevant examples and discussion. We reviewed various studies where scRNA-seq has helped identify dynamic cell subset transformations during tumorigenesis, modulate ME, epithelial-mesenchymal transition, and cancer stem cells enrichment, and identify novel signaling molecules, prognostic gene markers, and therapeutic vulnerabilities for PDAC. Identification of biomarkers such as Matrix metalloproteinase 1 (MMP1) and the S100A2+ tumor subset, characterization of the basal-like malignant subtype, and interventions like radiofrequency ablation reshaping the PDAC-ME were also discussed. Additionally, the roles of cancer associated fibroblasts and the therapeutic potential inhibitors in combination with signal transducer and activator of transcription 3 blockade and anti-CD47/anti-PD-L1 immunotherapy were reviewed in preventing PDAC resistance.

Bladder cancer is a prevalent malignancy of the urinary system. Urothelial carcinoma is the predominant type, accounting for more than 90% of cases. The remaining histologic types include squamous cell carcinoma (approximately 2%-7%) and adenocarcinoma (approximately 1%-2%). Within urothelial carcinoma, the papillary subtype is responsible for approximately roughly 70% of cases, and it is often linked to high-frequency gene mutations (e.g., FGFR3 and TP53) and epigenetic alterations, such as DNA hypermethylation-mediated silencing of genes, including RASSF1A and CDH1, and disruptions in histone modification attributable to histone deacetylase overexpression. Platinum-based chemotherapy remains the standard first-line treatment for advanced disease. However, recent research efforts have concentrated on targeted therapy, immunotherapy, metabolic reprogramming, and novel biotechnological applications. In particular, the dynamic interplay between tumor cell metabolic reprogramming and the immune suppressive tumor microenvironment, collectively termed the "metabolic-immune axis", constitutes a major challenge underlying drug resistance. This review summarizes how this axis, through mechanisms such as enhanced glycolysis and abnormal amino acid/lipid metabolism, influences bladder cancer progression and treatment responsiveness, thereby establishing a theoretical framework for future research directions.

Measurable residual disease (MRD) has become a central biomarker in acute leukemia, transitioning from a research tool to an essential component of clinical practice. Advances in multiparameter flow cytometry, quantitative PCR, and error-corrected next-generation sequencing have increased detection sensitivity to as low as one leukemic cell among 105-106 normal cells, far surpassing conventional morphology. Across acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), MRD negativity is consistently associated with lower relapse risk and superior survival. MRD status informs risk stratification, consideration of allogeneic hematopoietic stem cell transplantation, and post-remission monitoring strategies. In selected clinical contexts, most clearly MRD-positive B-cell ALL, MRD can serve as a trigger for therapeutic intervention, whereas in many AML settings MRD-directed intensification with targeted agents remains investigational and is best pursued within prospective trials. However, MRD implementation remains heterogeneous, and important challenges persist, including assay standardization, distinction between true residual leukemia and clonal hematopoiesis, and definition of optimal monitoring schedules and intervention thresholds. This review summarizes current MRD detection technologies, their prognostic and therapeutic implications in acute leukemia, and future directions for integrating MRD into individualized, biology-driven treatment algorithms.

Neuroblastoma (NB) is the most prevalent extracranial solid tumor in children. Therefore, urgent exploration of novel therapeutic targets and more effective approaches is imperative to enhance the prognosis of these children.

Ecotropic viral integration site 1 (EVI1), encoded by the EVI1 gene on chromosome 3q26.2, is a dual-domain zinc finger transcription factor that functions as a potent proto-oncogene in a wide spectrum of hematological malignancies. Under normal physiological conditions, its expression is tightly regulated and restricted primarily to hematopoietic stem cells and specific embryonic tissues. However, aberrant overexpression of EVI1 is a hallmark of aggressive myeloid leukemias, including acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and the blast crisis of chronic myeloid leukemia (CML). The oncogenic activation of EVI1 occurs through diverse genetic mechanisms, most notably chromosomal rearrangements involving the 3q26 locus, such as inv(3)(q21q26.2) and t(3;3)(q21;q26.2), which juxtapose the EVI1 gene with potent enhancers like that of GATA2. Other mechanisms include the formation of oncogenic fusion genes (e.g., AML1-EVI1, ETV6-EVI1), enhancer hijacking, and retroviral insertional mutagenesis. Once overexpressed, EVI1 drives leukemogenesis through multifaceted molecular actions. It acts as a master transcriptional regulator, profoundly disrupting normal hematopoietic differentiation by repressing key lineage-specific transcription factors like RUNX1 and interfering with cytokine-induced maturation. Concurrently, EVI1 promotes cell survival and proliferation by modulating critical signaling pathways, including the potent inhibition of the tumor-suppressive TGF-β pathway and the activation of the pro-survival PI3K/AKT/mTOR cascade via PTEN suppression. EVI1 also cooperates with a multitude of other oncogenic lesions, such as MLL rearrangements, AML1 mutations, and activated RAS signaling, to accelerate disease progression. Clinically, EVI1 overexpression is one of the most robust independent indicators of poor prognosis, associated with therapy resistance and reduced overall survival. This review provides a detailed discussion of the mechanisms underlying EVI1's activation, its complex molecular functions in hematopoietic transformation, and its profound clinical implications in hematological malignancies.

Cancer treatment is a significant challenge facing global medicine, with complex molecular mechanisms and drug resistance being key factors limiting treatment outcomes. Abnormal lipid metabolism is one of the important characteristics of tumors, providing metabolic support for the growth, proliferation, migration, and invasion of tumor cells. Tumor suppressor p53 protein and sterol O-acyltransferase 1 (SOAT1) play an important role in regulating cellular lipid metabolism and are closely related to the occurrence, development, and prognosis of various tumors. p53 protein regulates tumor lipid metabolism through multiple signaling pathways, while SOAT1, as a key enzyme in cholesterol esterification, is highly expressed in many tumors and accelerates tumor progression. Recent studies have shown that there may be a functional association between p53 protein and SOAT1, coordinating the regulation of lipid homeostasis in tumor cells. This article reviews the research progress on p53 protein and SOAT1 in tumor lipid metabolism, focusing on the potential mechanisms of action of the p53-SOAT1 axis in tumor development, and prospects its application prospects as a target for cancer treatment.
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Genomics-and genomic testing in particular-has transformed oncology, facilitating both targeted therapies and personalized care. In pediatric oncology, unique clinical and ethical considerations arise. Compared with adults, children and adolescents are affected by more limited evidence regarding test performance, variant interpretation, and the clinical utility of genomically informed interventions. Nevertheless, genomic findings may have implications beyond the patient, affecting their parents, siblings, and other relatives and raising questions around consent, assent, privacy, and psychosocial impact. This narrative review examines how ethical dimensions of genetic and genomic testing evolve across the pediatric cancer continuum, from diagnosis and treatment through survivorship and transition to adult care. Attention is given to communication strategies, interdisciplinary support, and equity concerns that influence the responsible integration of genomic medicine. The authors also identify priority areas for future inquiry, including incorporation of children's perspectives, longitudinal approaches to recontact and reconsent, and better understanding of how genomic information affects treatment decision-making. Pediatric genetic and genomic testing in oncology holds great promise, but its benefits can only be realized through thoughtfully developed and standardized communication practices, careful ethical deliberation, and equitable implementation. By proactively addressing these issues, pediatric oncologists can harness genomic advances in ways that respect and support children and their families.

The ubiquitin-proteasome system (UPS) is a crucial determinant of protein stability and activity in various aspects of physiological function and disease development. The well-characterized class of regulatory enzymes within the UPS is deubiquitinating enzymes (DUBs), and their effects, particularly those of the ubiquitin-specific proteases (USPs), oppose ubiquitination. All DUB activities can be more or less disrupted in various cancers, including breast cancer, and DUB alterations contribute substantially to tumor initiation, progression, and many forms of therapeutic resistance. In this review, we discuss the various molecular mechanisms of action of USPs on breast cancer hallmarks, including proliferation, aggression or metastasis, evasion of apoptosis, immune evasion, and metabolic programming. We evaluate how specific USPs stabilize oncogene members by deubiquitinating target proteins or deubiquitinating tumor suppressors, thereby influencing a variety of cellular behaviors, from regulating the cell cycle to modulating immune responses. Due to their important role in breast cancer pathology, the alterations of USP activities and the functional roles of selective USPs will also demonstrate some ways USPs present promising therapeutic targets in breast cancer. We will provide a comprehensive overview of USP inhibitors to date, focusing on their utilization in developing and describing efficacy in breast cancer models. Pharmacological inhibitors of specific USPs, such as pimozide, trifluoperazine, rottlerin, 6-thioguanine, and costunolide, are highlighted for their potential to inhibit proliferation, metastasis, induce apoptosis, and circumvent therapy resistance across breast cancer subtypes (triple-negative and HER-2 positive). The review highlights the complex and often contradictory roles of USPs in breast cancer and points to the immense promise of targeting these enzymes to develop new and efficacious anticancer therapies.

MAX is the essential binding partner of MYC, necessary for MYC-dependent transcriptional activation. Depending on the context, MAX can function as a tumor suppressor or promote tumorigenesis in an MYC-driven manner. Here, we highlight the key discoveries defining the role of MAX in cancer and the current research gaps.

Prostate cancer exhibits marked ethnic differences in genetic architecture. Although polygenic risk scores (PRS) and germline genetic testing have shown clinical utility in European populations, their applicability to Asian populations remains limited. This review synthesizes evidence published between 2020 and 2025 on PRS and germline genetics in Asian prostate cancer cohorts, focusing on Chinese, Japanese, and Korean populations. Recent studies demonstrate that population-specific PRS models effectively stratify prostate cancer risk in Asian men, with individuals in the highest decile showing a 4- to 5-fold increased risk. The 2025 BARCODE1 trial reported a 40.0% cancer detection rate, with 55.1% clinically significant disease, among PRS-selected European men, highlighting the need for population-specific validation in Asians. Germline profiling indicates that 25.1%-29% of Chinese patients harbor deleterious variants, most frequently involving BRCA2. Ethnic-specific susceptibility variants have also been identified, including HOXB13 G132E in Asians, contrasting with the G84E variant predominant in Europeans. The 2022 Hong Kong Consensus provides the first comprehensive guideline tailored to germline testing in Asian populations. Despite these advances, current PRS models primarily predict disease incidence rather than aggressive phenotypes. Key challenges include smaller genome-wide association study sample sizes, limited prospective validation, and heterogeneous clinical and research infrastructure across Asia. In conclusion, while substantial progress has been made in characterizing genetic risk in Asian prostate cancer, European-derived models show reduced accuracy. Future priorities include large-scale multiethnic collaborations, prospective validation studies, and development of predictors for aggressive disease.

T-cell receptors (TCRs) are generated through somatic recombination of variable (V), diversity (D), and joining (J) gene segments, resulting in an extraordinarily diverse receptor repertoire that is essential for immune surveillance and host defense. TCR sequencing (TCR-seq) has emerged as a powerful tool for comprehensive characterization of the adaptive immune repertoire, offering deep insights into T-cell diversity, antigen specificity, and clonal dynamics.TCR-seq enables the tracking of T-cell clones across both temporal and spatial dimensions. From a longitudinal perspective, it allows for the monitoring of clonal dynamics before and after therapeutic interventions or over the course of disease progression. Temporal shifts in clonal composition can reveal the persistence, contraction, or expansion of specific T-cell populations, thereby providing valuable information on the durability of immune responses and the efficacy of treatments. From a spatial standpoint, TCR-seq facilitates comparative analyses of repertoires across distinct anatomical compartments, including tumors, blood, and lymph nodes. Such analyses yield insights into tissue-specific immune responses, T-cell trafficking, and infiltration patterns. Moreover, the ability to track antigen-specific T-cell clones enables the visualization and quantification of tumor-specific immune responses. Advances in spatial TCR-seq now integrate spatial context with clonal identity and repertoire diversity, further illuminating complex immune architecture within tissue microenvironments. Nonetheless, despite the development of various approaches for antigen specificity prediction, further advances are needed to improve their accuracy and generalizability.A wide range of TCR-seq platforms are currently available, including DNA-based and RNA-based protocols, short-read and long-read sequencing technologies, and bulk and single-cell approaches. Each method presents unique advantages in terms of resolution, throughput, cost, and biological relevance. For instance, DNA-based TCR-seq is well suited for longitudinal tracking of clonal populations, whereas RNA-based approaches are advantageous for detecting actively transcribed, antigen-responsive clones. Short-read sequencing offers high-throughput capabilities, while long-read and paired-chain sequencing provide comprehensive structural and functional information on TCRs. Additionally, computational methods, including machine learning algorithms and motif-based clustering, are increasingly employed to infer antigen specificity directly from TCR-seq data.In this review, we examine the current landscape of TCR-seq through the lenses of what, when, where, why, and how, highlighting recent technological developments and emerging applications that are shaping the field of immune repertoire analysis.

Cuproptosis, a copper-dependent regulated cell death pathway, and long non-coding RNAs (lncRNAs) are pivotal emerging regulators in cancer biology. This review proposes an integrative"cuproptosis-lncRNA axis" as a central network governing tumor immunity, prognosis, and therapy sensitivity. We introduce a functional taxonomy, classifying cuproptosis-related lncRNAs into three functional archetypes:ceRNA sponges, epigenetic regulators, and signaling hubs. We elucidate how each category fine-tunes copper homeostasis, mitochondrial proteotoxic stress, and downstream malignant phenotypes. This axis uniquely bridges mitochondrial metabolism, cell death execution, and immune modulation, offering a novel conceptual framework for understanding cancer progression. We further discuss how targeting this axis-through strategies tailored to lncRNA functional class-can overcome immune evasion and chemoresistance, providing a roadmap for precision oncology. The emerging concept of "copper immunometabolism" within the tumor microenvironment is also highlighted. The integration of cuproptosis-directed therapies with lncRNA targeting holds significant promise for developing more effective, personalized cancer treatments.

Protein tyrosine phosphatases (PTPs), pivotal regulators of tyrosine phosphorylation dynamics, orchestrate cellular signaling networks to govern fundamental processes such as hematopoietic stem cell (HSC) quiescence, proliferation, and stress responses. Dysregulation of PTPs disrupts tyrosine phosphorylation homeostasis, culminating in HSC dysfunction, malignant transformation and leukemogenesis through aberrant activation of oncogenic pathways. This review summarizes the recent advances in understanding PTP-mediated mechanisms underlying HSC maintenance and leukemogenesis, with a focus on their dual roles as tumor suppressors and context-dependent oncogenic drivers. It could help explore the molecular mechanism of normal hematopoietic homeostasis and provide potential therapeutic targets of the related blood diseases.

UHRF1 (ubiquitin-like with PHD and RING finger domains 1) is a multi-domain epigenetic regulator that integrates DNA methylation, histone modification, and ubiquitin signaling. Its overexpression is consistently observed across diverse cancers, where it silences tumor suppressor genes, stabilizes oncogenic proteins, and rewires metabolic and stress pathways, thereby driving tumor progression and therapy resistance. Targeting UHRF1 offers a domain-specific and context-dependent strategy distinct from global demethylation, reducing off-target toxicity and providing a refined therapeutic window. Natural compounds such as flavonoids, berberine, and thymoquinone, as well as synthetic inhibitors of reader domains, proteasomal degraders, and RNA-based approaches, have demonstrated potential to disrupt UHRF1 function. UHRF1 inhibition may also synergize with DNMT or HDAC inhibitors, immune checkpoint blockade, and ferroptosis inducers. Current evidence supports UHRF1 as both a biomarker and a promising druggable target for next-generation epigenetic cancer therapies.

Mitochondrial transcription factor A (TFAM) is indispensable for mitochondrial DNA (mtDNA) maintenance and transcription, governing cellular bioenergetics. Despite its known physiological importance, TFAM plays a complex and often paradoxical role in cancer biology. This study integrates pan-cancer bioinformatics analyses with experimental evidence to comprehensively elucidate TFAM's multifaceted impact on tumorigenesis. We systematically investigated the heterogeneity of TFAM across diverse cancer types, specifically focusing on its regulatory mechanisms in metabolic reprogramming, signal transduction, and immune microenvironment remodeling. Our analysis reveals that TFAM functions as a critical node connecting mitochondrial integrity to tumor progression, balancing tumor-promoting and tumor-suppressive roles depending on the context. Finally, we discuss the challenges of targeting TFAM, such as off-target toxicity, and highlight emerging precision oncology strategies, including mitochondria-targeted delivery systems, that aim to exploit these mitochondrial vulnerabilities.

Protein lipidation and ubiquitination are two fundamental post-translational modifications that orchestrate protein localization, stability, and function. Beyond their independent roles, emerging evidence reveals a complex crosstalk between these modifications that profoundly shapes tumor biology. Lipidation promotes membrane anchorage and functional activation of key oncogenic drivers, whereas ubiquitination dynamically controls protein abundance through proteasomal degradation or signaling modulation. Their interplay regulates pivotal processes in cancer, including immune evasion, tumor microenvironment remodeling, metabolic reprogramming, invasion and metastasis, and uncontrolled proliferation. Mechanistically, lipidation can shield proteins from ubiquitin-mediated degradation or recruit deubiquitinases, while ubiquitination governs the turnover and activity of lipidation enzymes, together forming a dynamic antagonistic-synergistic network. Recent advances highlight the therapeutic promise of targeting this axis: inhibitors of NMTs, DHHC enzymes, and lipidation-dependent pathways, as well as ubiquitin-based technologies such as PROTACs, DUB inhibitors, and molecular glues, are being developed toward clinical translation. By integrating mechanistic insights with therapeutic innovation, this review underscores lipidation-ubiquitination crosstalk as a critical regulatory hub and potential dual-modification target for precision oncology.

Follicular lymphoma (FL) is a common type of non-Hodgkin lymphoma typically characterized by a nodular growth pattern and the t(14;18) translocation. A rare variant, FL with a predominantly diffuse growth pattern (dFL), lacks this translocation, demonstrates diffuse architecture, and is frequently associated with deletion of 1p36.

Fibronectin 1 (FN1), located on chromosome 2q35, encodes fibronectin, a high molecular weight glycoprotein of the extracellular matrix. Several histologically overlapping chondroid matrix-producing tumors are known to harbor FN1 rearrangements, including soft tissue chondroma, synovial chondromatosis, calcifying aponeurotic fibroma, calcified chondroid mesenchymal neoplasm and phosphaturic mesenchymal tumor. Over the past 10 years, fusions involving the FN1 gene have also been identified in other mesenchymal neoplasms such as lipofibromatosis and inflammatory myofibroblastic tumor. The current World Health Organization Classification of Soft Tissue and Bone Tumors suggests that FN1-rearranged lesions are typically benign or intermediate. This review provides an updated overview of the clinical, histological and molecular genetic features of FN1-rearranged mesenchymal neoplasms and discusses their relationships with one another.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancers, characterized by pronounced cellular heterogeneity, a dense desmoplastic stroma, and a highly immunosuppressive tumor microenvironment (TME). Recent advances in single-cell RNA sequencing (scRNA-seq) have reshaped our understanding of PDAC by characterizing its cellular composition at single-cell resolution. These studies have uncovered complex TME networks involving T cells, myeloid populations, fibroblasts, and malignant epithelial cells, and have provided mechanistic insights into immune evasion, metastatic progression, and therapeutic resistance. Collectively, these findings depict PDAC as a dynamic and interactive ecosystem driven by cellular interactions. In this review, we systematically summarize recent scRNA-seq-based studies addressing PDAC heterogeneity, tumorigenesis, immune remodeling, therapeutic resistance and biomarker discovery. We further discuss integrative single-cell and spatial multi-omics approaches to map the TME of PDAC, providing a framework for understanding PDAC biology at single-cell and spatial resolution.