Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. Despite major advances in therapy, the treatment of ALL remains a significant challenge. Therapeutic protocols are based on the use of combinations of chemotherapeutic drugs. While such combinations increase treatment efficacy, they also complicate the assessment of toxicity. It should be noted that the variability in the occurrence of toxic responses to ALL therapy in children may be determined by the presence of gene variants that influence both the pharmacokinetics and pharmacodynamics of chemotherapeutic drugs. This review summarized and analyzed the most significant and well-studied pharmacogenetic markers to date associated with the toxicity and response to chemotherapeutic agents used in the treatment of pediatric ALL. In particular, pharmacogenetic markers for the following drugs were analyzed: anthracyclines (doxorubicin, daunorubicin), vincristine, glucocorticoids (prednisone, dexamethasone), L-asparaginase, methotrexate, alkylating agents (cyclophosphamide, ifosfamide), 6-mercaptopurine, cytarabine, and etoposide. At present, only a few genes, TPMT and NUDT15, have well-established clinical utility, whereas the clinical relevance of pharmacogenetic markers for other drugs used in pediatric ALL therapy remains under investigation. The review also highlights the main knowledge gaps in current research and outlines promising directions for future studies aimed at integrating pharmacogenetic testing into clinical practice for personalized treatment of ALL.

Human papillomaviruses (HPVs) cause diverse cutaneous and mucosal diseases, with several genotypes strongly associated with cervical cancer. Beyond the well-established role of cellular microRNAs (miRNAs) in gene regulation, increasing evidence shows that HPV also encodes its own viral miRNAs (v-miRNAs). These v-miRNAs modulate both viral and host gene expression, influencing key pathways involved in oncogenesis, including cell cycle control, apoptosis, immune evasion, and epithelial - mesenchymal transition. By shaping these regulatory networks, HPV-derived miRNAs promote viral persistence and contribute to malignant transformation. Their stability and specificity also make them promising biomarkers for cervical cancer diagnosis and prognosis, although clinical translation remains challenging. This review provides an updated overview of HPV-encoded miRNAs, their validated molecular targets, and their roles in tumour development. It also highlights emerging therapeutic strategies and future perspectives for integrating miRNA-based approaches into precision oncology for HPV-related cervical cancer.

Epithelial ovarian cancer (EOC) describes a group of diseases characterized by differing pathogeneses, molecular profiles, histologies and prognoses. The low incidence of each distinct histological type of EOC poses challenges for obtaining an accurate diagnosis, robust evidence to guide management, and a mechanistic understanding to ensure availability of effective therapies. Most EOCs, including high-grade serous ovarian cancer, predominantly originate from the fimbriated ends of the fallopian tube, whereas low-grade serous, clear cell, endometrioid and mucinous EOCs are thought to originate from other tissues. Despite recognized genetic susceptibilities for the disease, no effective screening is available and late-stage diagnosis remains common. Known genetic susceptibilities are addressed by risk reduction surgery including removal of both fallopian tubes and both ovaries. Management is predominantly based on adequate surgery and chemotherapy with carboplatin and paclitaxel, with the addition of anti-angiogenic therapy as indicated. The incorporation of poly(ADP-ribose) polymerase inhibitors into first-line therapy has considerably altered outcomes in some women with EOC who have defective homologous recombination DNA repair, including in those with BRCA1 and/or BRCA2 mutations. Other molecular characteristics are important in distinct types of EOC, but the use of matched targeted therapies remains under investigation, as does the role of immunotherapy for EOC, for which trial data have been disappointing to date. Translationally enriched clinical trials will be important to further explore and validate accurate biomarkers to better guide clinical care.

Protein lactylation emerges as a pivotal metabolic rheostat, translating microenvironmental lactate flux into stable programs that orchestrate cancer treatment resistance. This review synthesizes recent advances under the framework of "Lactylation Switch in Cancer Vulnerabilities." We dissect the dominant enzymatic pathways (AARS1/2, KATs, HDACs) and non-enzymatic mechanisms (MGO/LGSH), alongside their critical structural underpinnings. Furthermore, we delineate how lactylation signals are interpreted by specific readers (e.g., TRIM33), directly reprogram non-histone protein function through structural metamorphosis (e.g., disrupting p53, enhancing XLF), and engage in complex crosstalk with other PTMs, as exemplified by the synergistic interplay between histone H3 lysine 18 lactylation (H3K18la) and histone H3 lysine 27 acetylation (H3K27ac) in T-cell acute lymphoblastic leukemia (T-ALL). This interplay coordinately drives metabolic-epigenetic reprogramming, which specifically rewires intra- and extratumoral survival mechanisms. Lactylation fundamentally establishes a therapy-adaptive state by simultaneously enhancing intrinsic resistance (e.g., BLM K24la-mediated DNA repair) and extrinsic resistance (e.g., histone lactylation-driven PD-L1 upregulation). Critically, preclinical and clinical studies in validated models demonstrate that targeting this lactylation network (e.g., LDHA inhibition with stiripentol, KAT inhibitors, or site-specific blockers) yields striking synergistic effects, potentiating tumor sensitivity to chemotherapy, radiotherapy, and immunotherapy. Looking forward, we outline key translational paths, including deciphering stringent enzyme-substrate specificity for targeted inhibition, developing structure-based drug design, leveraging lactylomic signatures as predictive biomarkers, and addressing current mechanistic and technological gaps. This work not only establishes lactylation as a central mechanism of therapeutic resistance but also provides a novel conceptual paradigm for understanding how metabolic signals dynamically encode cancer cell vulnerabilities, offering transformative opportunities for precision oncology. Created in BioRender. Chengjiao, Y. (2026) https://BioRender.com/0lbu6jy .

Many studies using measured Body Mass Index (BMI) report an inverse association with lung cancer, but a few recent Mendelian randomization (MR) studies using genetically proxied BMI suggest a possible risk association. The aim of this study was to systematically evaluate and synthesize evidence on the association between lung cancer risk and both directly measured (i.e., clinically measured or self-reported) and genetically proxied BMI.

Caspase-1, a cysteinyl aspartate-specific protease central to inflammasome activation, acts as a master regulator of multiple programmed cell death (PCD) pathways including pyroptosis, apoptosis, necroptosis, ferroptosis, and PANoptosis. It interacts with other caspases and is tightly modulated by epigenetic mechanisms and post-translational modifications. During the tumor microenvironment and immune metabolic regulation, it is activated and acts in a context-dependent way. Given this multifaceted involvement in cancer, neurodegenerative diseases and autoimmune disorders, caspase-1 represents a promising yet challenging therapeutic target. Despite extensive research, challenges persist in the insufficient understanding of crossover mechanisms and research of caspase-1 inhibitors. This review systematically clarifies its paradoxical roles by integrating caspase-1' s regulatory and context-dependent networks across PCD, epigenetics, tumor microenvironment, immune metabolism, and diverse diseases. Additionally, we summarize therapeutic progress and root causes of caspase-1 inhibitors' clinical failure as well as putting forward some innovative treatment strategies, aiming to offer new perspectives for future treating design.

Nucleosome spacing patterns in the genome form a unique signature of a given cell, reflecting its chromatin organization and gene expression. Recently, studies of nucleosome spacing have expanded substantially due to the development of novel experimental tools and increased analysis of human samples. This has yielded thousands of high-resolution nucleosome maps across many species and cell types, as well as multiple human datasets that span across different ages and health conditions. With the rapid increase in nucleosome mapping data, their analysis and interpretation have become critically important. Indeed, several discrepancies in nucleosome spacing have been reported recently, using different experimental methods. However, when nucleosome spacing is consistently analysed, it can be linked to biologically important processes: (i) active genomic regions are characterized by shorter distances between nucleosomes in comparison to inactive regions; (ii) cancer cells tend to have shorter distances in comparison to normal cells of the same type; and (iii) ageing usually increases distances between nucleosomes. In many cases, the underlying molecular mechanisms remain to be clarified. Here, we provide a critical analysis of this field, focusing on nucleosome spacing in different types of genomic regions and cell types, as well as changes in cell differentiation, cancer, and ageing.

Retinoblastoma (RB), which is the most common pediatric intraocular malignancy driven by RB1 inactivation, presents with clinical challenges, such as treatment toxicity, relapse, and resistance. Traditional models inadequately replicate human RB genetics or tumor heterogeneity, warranting the development of advanced in vitro platforms. Retinal organoids generated from human pluripotent or patient-specific stem cells enable three-dimensional(3D) modeling of the tumor microenvironment, drug screening, and mechanistic studies. This review summarizes RB pathogenesis, including RB1 loss, MYCN amplification, epigenetic dysregulation (e.g., METTL3-mediated m6A), and dysregulated pathways (PI3K/AKT/mTOR, Hedgehog), and highlights CRISPR-engineered organoids for identifying cone precursors as tumor origins and validating therapies (CDK4/6 inhibitors and sunitinib). Despite these advances, organoid applications are limited by high costs, variable success rates, incomplete immune/vascular mimicry, and limited scalability. Current microfluidic systems partially address vascularization but lack functional perfusion. Future efforts should integrate multiomics, refine vascularization via 3D bioprinting, and develop immunocompetent models to address the disparity between preclinical research and clinical application. Organoid technology has the potential to advance personalized therapies and ultimately enhance the survival and quality of life of patients with RB worldwide.

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.