Human papilloma virus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) remains a challenging disease with poor prognosis. Circulating tumor DNA (ctDNA) has emerged as a promising biomarker to improve risk stratification, detect minimal residual disease (MRD), and guide treatment adaptation. This review synthesizes recent advances in ctDNA technologies and their clinical relevance for HPV-negative HNSCC.

Triple negative breast cancer (TNBC) is an aggressive BC subtype with limited therapeutic options and poor clinical outcomes. This subtype accounts for 15‑20% of all BC cases and contributes to nearly 40% of BC mortalities. The chemokine C‑X‑C motif ligand 1 (CXCL1) is a key player in TNBC progression through several signaling pathways, including NF‑κB, MAPK and related cascades. CXCL1 contributes to tumor growth, metastasis, immune modulation and resistance to therapy, however its role and therapeutic potential in TNBC has not been comprehensively described. The present review aimed to summarize CXCL1 biology in TNBC, with a focus on its prognostic relevance, role in the tumor microenvironment and potential as a therapeutic target, as well as emerging strategies aimed at modulating CXCL1 signaling. However, challenges remain in translating these findings into clinical application, including incomplete understanding of certain molecular mechanisms underlying CXCL1 function, unclear prognostic value, the need for validation of potential inhibitors in large and diverse cohorts and the lack of well‑designed clinical trials testing CXCL1‑targeted approaches. Addressing these challenges through rigorous preclinical work and carefully designed clinical trials is key to define the true therapeutic potential of CXCL1 in TNBC to advance precision medicine strategies and enhance clinical outcomes in patients with TNBC.

Claudin‑7 (CLDN7) is a key component of epithelial tight junctions. It plays a vital role in maintaining cell polarity, barrier integrity and paracellular transport. Abnormal CLDN7 expression is closely related to the onset and progression of various diseases. It is especially markedly associated with the growth and metastasis of multiple cancers. Additionally, dysregulated CLDN7 expression contributes to the progression of intestinal, skin and respiratory system diseases. The present review summarized the structure, expression, physiological functions, stability and regulatory mechanisms of CLDN7, emphasizing its role in tumors. The expression patterns, regulatory mechanisms, effect on malignant phenotypes and clinical significance of CLDN7 were also discussed.

Remaining challenges in management of patients with germ cell tumors (GCTs) include selecting the optimal treatment modality in patients with early metastatic disease, biomarker development and developing newer treatments in patients with refractory disease. This review aims to highlight recent developments in these domains.

PARP inhibitors (PARPi) have rapidly reshaped the treatment landscape for metastatic prostate cancer, moving from biomarker-selected monotherapy in metastatic castration-resistant prostate cancer (mCRPC) to first-line combination strategies with androgen receptor pathway inhibitors (ARPIs) and more recently, into metastatic hormone-sensitive disease (mHSPC). This review summarizes the evidence-based use of PARPi in metastatic prostate cancer, integrating the mechanistic rationale and guideline perspectives. We also highlight the resistance mechanisms that inform patient selection and underpin emerging strategies.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with a dismal 5‑year survival rate of ~9%, primarily due to late diagnosis, aggressive metastasis and profound resistance to conventional therapies. Epithelial‑mesenchymal transition (EMT) has been identified as a pivotal driver of these malignant phenotypes, facilitating early invasion, dissemination and treatment failure. The present review systematically elaborated on the multidimensional mechanisms underlying EMT in PDAC, emphasizing its operation as a spectrum of hybrid epithelial/mesenchymal states rather than a binary switch. Key molecular mechanisms include the activation of core transcription factors (such as Snail, ZEB, Twist), intricate crosstalk within the tumor microenvironment (such as transforming growth factor-β and hepatocyte growth factor signaling from stromal cells) and dynamic epigenetic reprogramming. Furthermore, EMT critically contributes to the acquisition of cancer stem cell properties and enhances the survival and colonization of circulating tumor cells. The present review also outlined emerging translational strategies targeting EMT‑related pathways, highlighting agents such as STNM01 that have entered early-phase clinical trials. By synthesizing unprecedented insights into EMT's plastic spectrum states and subtype‑specific regulatory networks, this work establishes a paradigm‑shifting framework for advancing EMT‑targeted therapies; offering transformative potential to overcome PDAC's historical therapeutic barriers and substantially improve patient survival outcomes. By synthesizing current insights from molecular pathways to therapeutic applications, the present review confirmed EMT as a promising therapeutic target and provides a strategic framework for advancing PDAC treatment, with the ultimate goal of improving clinical outcomes.

Colorectal cancer (CRC) remains a major global health concern, with a rising incidence among younger adults and persistently high mortality in advanced stages, despite significant scientific and technological progress. Its etiology is multifactorial, involving lifestyle factors, genetic susceptibility, chronic inflammation, and gut microbiome dysbiosis. Recent advances in screening, molecular profiling, surgery, and systemic therapies have substantially reshaped CRC management. This narrative review was conducted through a comprehensive literature search of PubMed/MEDLINE, Scopus, and Web of Science databases, covering publications from January 2015 to June 2025. Peer-reviewed articles addressing CRC epidemiology, molecular pathways, screening and diagnostic strategies, surgical management, systemic therapies, and emerging treatment modalities were selected. Evidence was qualitatively synthesized and organized into clinically relevant thematic domains. Recent progress in CRC screening, including advanced endoscopic imaging, fecal DNA testing, and blood-based biomarkers, has improved early detection, although implementation remains uneven. Molecular characterization such as MSI-H/dMMR status, RAS/RAF mutations, HER2 amplification, and consensus molecular subtypes â?" guides prognostic assessment and personalized therapy. Surgical resection remains the cornerstone of curative-intent treatment, with minimally invasive and robotic approaches reducing morbidity while maintaining oncologic safety. Techniques such as complete mesocolic excision and total mesorectal excision, along with multimodal strategies for advanced disease, have expanded therapeutic options. Despite these advances, challenges persist, including therapeutic resistance, tumor heterogeneity, limited immunotherapy efficacy in microsatellite-stable disease, and rising early-onset CRC. Future progress relies on precision medicine, ctDNA-guided monitoring, microbiome-targeted strategies, and optimized surgical selection.

IL‑6, a pleiotropic inflammatory cytokine predominantly secreted by fibroblasts, myeloid‑derived suppressor cells, tumor‑associated macrophages and tumor cells, is associated with poor prognosis of and therapeutic resistance in non‑small cell lung cancer (NSCLC). The activation of signaling pathways, including the JAK/STAT3, MAPK and PI3K/AKT pathways, promotes tumor survival. Furthermore, the IL‑6/JAK/STAT3 signaling axis has emerged as a key driver of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‑TKI) resistance, orchestrating intricate crosstalk within the tumor microenvironment (TME) to promote cell survival and immunosuppression. The present review synthesized current evidence on the dual role of IL‑6 in mediating EGFR‑TKI resistance and blunting anti‑tumor immunity. The present review highlights the preclinical rationale for combining IL‑6 blockade with EGFR‑TKI or immune checkpoint inhibitors to overcome refractory disease. The present review also highlights the structure, molecular mechanisms and clinical insights of IL‑6 in the TME of EGFR‑mutant NSCLC and may provide optimized therapeutic strategies for EGFR‑TKI‑refractory NSCLC.

Diffuse large B‑cell lymphoma (DLBCL), the most prevalent subtype of lymphoma, is characterized by rapid growth and a poor prognosis, with the R‑CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) being the standard first‑line therapy. However, 30‑40% of patients experience early relapse or refractoriness to treatment, highlighting the need to understand the mechanisms of chemoresistance. The present review synthesizes the current knowledge on the molecular mechanisms underlying chemoresistance in DLBCL, including genetic mutations, epigenetic modifications, aberrant activation of signaling pathways, alterations in drug metabolism and efflux, and upregulation of anti‑apoptotic proteins. In addition, the role of the tumor microenvironment in mediating therapeutic resistance is discussed and biomarkers associated with chemoresistance are explored. Furthermore, novel therapeutic strategies targeting chemoresistance, such as immunotherapy, metabolic modulators and epigenetic therapies, are examined. Understanding these mechanisms is crucial for developing effective treatment strategies to overcome resistance and improve patient outcomes in DLBCL.

The present review focuses on the molecular functions of prostate‑specific membrane antigen (PSMA) as a biologically active protein. Its clinical use as a positron emission tomography imaging marker or radioligand therapy target is beyond the scope of the current review. The role of PSMA (also known as folate hydrolase 1/glutamate carboxypeptidase II/N‑acetylated‑α‑linked acidic dipeptidase) has progressed from that of a prostate cancer biomarker to a functional driver of tumor biology. Structurally, PSMA is a type II transmembrane glycoprotein with glutamate carboxypeptidase and folate hydrolase activities, linking glutamate and one‑carbon metabolism to proliferation, redox balance and epigenetic regulation. PSMA undergoes clathrin‑dependent endocytosis and interacts with various scaffolding proteins, such as filamin A and receptor for activated C kinase 1, which are properties that underlie its functional role as a molecular signaling hub, in addition to being a therapeutic entry point. Its expression is dynamically regulated by androgen receptor signaling, NF‑κB activation and epigenetic modifiers, contributing to intra‑patient heterogeneity and treatment resistance. PSMA expression is not restricted to prostate epithelium but is also expressed in tumor‑associated endothelium across multiple malignancies, where it can promote angiogenesis through integrin/PI3K‑AKT‑mTOR signaling and paracrine induction by extracellular vesicles. These molecular functions can result in immune exclusion, stromal activation and neuronal interactions, positioning PSMA as a key regulator of the tumor microenvironment. Although PSMA‑targeted imaging and therapies have demonstrated substantial clinical utility, understanding the biological basis of the function of PSMA is essential for interpreting the heterogeneous clinical responses and for designing next‑generation therapeutic strategies in association with this protein. By integrating enzymatic activity, non‑enzymatic scaffold signaling and tumor microenvironmental regulatory information, the present review provides a functional framework in the PSMA biology field and discusses how these molecular properties can be leveraged to develop novel rational and effective PSMA‑targeted interventions.

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.