Thyroid cancer represents the fastest-growing endocrine malignancy worldwide, with papillary thyroid carcinoma (PTC) being its predominant pathological subtype. RET fusion is a key driver genetic alteration in PTC, closely associated with enhanced tumor invasiveness and poorer prognosis in some cohorts. This review systematically summarizes the molecular pathogenesis of RET fusion-positive PTC, encompassing the structure and function of the RET proto-oncogene and its encoded protein, the molecular characteristics of fusion events (predominantly CCDC6-RET and NCOA4-RET), the mechanisms underlying sustained activation of classical signaling pathways, and the novel regulatory mechanism of liquid-liquid phase separation. Furthermore, the review elaborates on the clinical efficacy of highly selective RET inhibitors (selpercatinib and pralsetinib), including their breakthroughs in pediatric patients and radioactive iodine-refractory cases. Primary and acquired resistance mechanisms (on-target mutations, bypass activation) and corresponding strategies (next-generation inhibitors, combination therapies) are also analyzed. By integrating recent advances in basic and clinical research, this review provides a comprehensive reference for the precision diagnosis and treatment, mechanistic investigation, and drug development for RET fusion-positive PTC.

Advancements in profiling technologies have deepened our understanding of cancer biology, particularly in non-small cell lung cancer (NSCLC). Genomic data have demonstrated profound clinical impact, enabling the rational design of therapeutics and achieving excellent clinical outcomes for patients with oncogene-addicted disease. While proteomics, transcriptomics, epigenetics, metabolomics, and microbiomics have also generated a wealth of data in NSCLC, their clinical impact is comparatively limited. The increasing use of multiomic profiling has the capacity to change this paradigm, offering new opportunities for improving patient care, particularly for those with non-oncogene-addicted (NOA) NSCLC. This review will summarize the current landscape of multiomic research in NSCLC, emphasizing the potential role in precision oncology. Each omic field is discussed in turn, describing potential clinical applications and challenges of each. In addition, the developing fields of spatial-omic and integrated multiomics, which are becoming increasingly important in understanding cancer biology, are discussed. NSCLC samples have been extensively profiled across different omic technologies, revealing a range of biomarkers associated with prognosis or response to therapy and potential drug targets, many of which are being investigated. While the patient groups analyzed differ between studies, most are performed on early-stage resection samples, and many studies do not stratify results by genomic status, limiting our understanding of NOA-NSCLC. In addition, while many studies independently analyze several omics, fewer use multiomic integration algorithms. Despite significant research into spatial-omic and multiomics in NSCLC, only genomics has significantly affected NSCLC clinical care, leaving an unmet need in NOA-NSCLC. However, nongenomic technologies have significant potential for precision oncology, particularly when used alongside multiomic integration to discover biomarkers or to identify future precision medicine targets.

Glioblastoma (GBM) leverages exosomes to drive tumor progression, immunosuppression, and therapy resistance through transfer of oncogenic miRNAs, circRNAs, and proteins. These vesicles reprogram the tumor microenvironment (TME) by activating pathways such as TREM1 in microglia and STAT3-mediated vasculogenic mimicry. Exosomal nucleic acids, including circZNF800 and miR-374b-3p, serve as non-invasive biomarkers for recurrence and treatment monitoring. Advances in engineering, such as Angiopep-2-functionalized exosomes for blood-brain barrier penetration and CRISPR-Cas9-loaded vesicles targeting resistance genes, highlight their therapeutic potential. Challenges in heterogeneity, standardization, and scalable production underscore the need for interdisciplinary innovation to translate exosome-based strategies into clinical practice.

The set of somatic mutations present in a human tumor is a record of one or more mutational processes, each of which leaves distinct "signature" of mutation types. Mutation types can be classified in various ways, the most straightforward being the base change induced by a single-base substitution (e.g., C>A, T>G, etc.). The advent of high-throughput DNA sequencing has facilitated the comprehensive, genome-wide assessment of mutation types in human tumors. This has spurred the development of methodology to tease apart the relative contribution of each mutational process by decomposing the set of all mutations into individual signatures. Many mutational signatures have known etiologies. Therefore, mutational signature inference can shed light on the causes of cancer and inform patient treatment. To date, most studies in this area have been performed on solid tumors; consequently, the application of existing methods to hematological cancers has yielded limited results. In this review, we provide an overview of the history and methodology behind mutational signature inference. Here, we present the challenges inherent in its application to hematological cancers and survey the work performed thus far. We highlight how recent research analyzing mutational signatures in normal blood cells can elucidate the beginning of a continuum of mutational processes, from normal hematopoiesis through mature hematological malignancy. Accurate characterization of mutational signatures in cancer development may aid in clinical diagnosis, prognosis, and treatment decisions.

Colorectal cancer is a leading cause of cancer mortality characterised by a unique metabolic microenvironment and complex interactions with the gut microbiota. Lactylation, a novel post-translational modification derived from lactate, has emerged as a key epigenetic regulator connecting metabolic reprogramming to gene expression. While its general roles in cancer are recognised, the tissue-specific regulatory network of lactylation in colorectal cancer-particularly its interplay with the gut microbiome and specific chemotherapy resistance mechanisms-remains underexplored.

Brain tumors represent some of the most formidable challenges in neuro-oncology due to their aggressive clinical course, resistance to therapy, and profound molecular heterogeneity. Among the emerging regulatory elements reshaping our understanding of tumor biology are long non-coding RNAs (lncRNAs), a diverse class of RNA transcripts that modulate gene expression and cellular behavior without encoding proteins. This review provides an in-depth and integrative examination of the biogenesis, regulatory mechanisms, and functional roles of lncRNAs in brain tumor development and progression. We systematically explore both canonical and non-canonical pathways of lncRNA biogenesis, detailing how these influence structural specificity and molecular interactions. This review synthesized evidence retrieved from PubMed/MEDLINE, Scopus, and Web of Science, covering publications from January 2010 to June 2025. This analysis highlights key gaps, such as context-dependent therapeutic effects that limit translational applicability. A major focus is placed on the interplay between lncRNAs and core oncogenic signaling pathways, including Phosphoinositide 3-kinase (PI3K)/serine/threonine kinase (AKT), Signal Transducer and Activator of Transcription 3 (STAT3), Wingless/Int-1 (Wnt)/β-catenin, and Transforming Growth Factor-Beta (TGF-β), which drive malignant transformation, invasion, stemness, and therapeutic resistance in gliomas. Furthermore, we dissect the molecular functions of lncRNAs as epigenetic regulators, competitive endogenous RNAs (ceRNAs), and structural scaffolds, and discuss their contribution to the dynamic tumor microenvironment. By synthesizing the latest findings, this review underscores the academic and translational importance of targeting lncRNA-associated networks. It also highlights emerging therapeutic approaches, such as antisense oligonucleotides, RNA interference, CRISPR-Cas systems, and natural lncRNA-modulating compounds, which collectively represent a promising frontier in precision medicine for brain tumors. This work offers a critical framework for future research and therapeutic innovation in the lncRNA landscape of neuro-oncology.

The 14-3-3 biomolecules are highly conserved acidic eukaryotic proteins responsible for many cellular pathways, including cell cycle regulation, cell migration, and gene transcription control. Dysregulation of these proteins has been linked to the onset or suppression of cancers. Explorative studies have shown the positive and negative correlations between 14 and 3-3 proteins and oncomiRs or tumor suppressor miRNAs in cancer cells and supportive tissues during tumorigenesis, tumor progression, and metastasis. Understanding the interactions between 14 and 3-3 proteins and various miRNAs is crucial in introducing these proteins as novel prognostic cancer biomarkers. Furthermore, understanding the tumor-associated biological functions of 14-3-3 family proteins and targeting their interaction with specific miRNAs or directly manipulating 14-3-3 proteins may reveal their potential for cancer treatment in the future, as discussed in this review.

The eukaryotic translation initiation factor 3 (eIF3) is the largest and most complex initiation factor in eukaryotes, functioning as a central hub that integrates signals from cellular stress, metabolism, and developmental pathways to regulate mRNA translation. Recent advances have uncovered subunit-specific roles of eIF3 that extend beyond canonical cap-dependent translation to include specialized mechanisms such as selective mRNA recruitment, noncanonical cap recognition, and translation elongation. This review summarizes the current mechanistic understanding of the contribution of aberrant eIF3 activity to diverse disease processes, including oncogenesis, neurodevelopmental and neurodegenerative disorders, muscle pathology, and infectious disease. We evaluate therapeutic strategies aimed at modulating eIF3 function, including subunit-selective small molecules, RNA-based therapeutics, and CRISPR-based interventions. We discuss the therapeutic promise of both inhibitory approaches-targeting oncogenic or pathogen-hijacked eIF3-and restorative strategies to correct genetic loss-of-function in neurological disease. Finally, we outline key challenges and opportunities for clinical translation, including tissue-specific delivery, subunit selectivity, and the identification of predictive biomarkers. eIF3 emerges as a versatile and druggable node in translational control with broad relevance across human disease.

Speckle-type POZ protein (SPOP) functions as a substrate adaptor within the cullin 3-based E3 ubiquitin ligase complex, playing an essential role in regulating diverse cellular processes by targeting specific proteins toward ubiquitination and proteasomal degradation. Aberrations in SPOP-driven proteolytic pathways have been implicated in the initiation and progression of prostate cancer. In this context, SPOP appears to function largely as a tumor suppressor by mediating the degradation of several oncogenic proteins such as AR, SRC3, CDC20, MYC, ERG, PD-L1, and BRD4. Mutations that impair SPOP function can result in the promotion of these substrates' oncogenic function, contributing to tumor initiation and progression. Hence, a deeper investigation into the molecular mechanisms of SPOP in prostate cancer will provide novel insights into its physiological function in oncogenesis and drug development. In this review, we summarize SPOP's tumor suppressor functions and structural features, upstream regulatory mechanisms, and SPOP-targeting therapeutic strategies in prostate cancer.

Cancer cells reprogram their metabolism not only through genetic mutations but also via reversible epigenetic modifications that alter gene expression without changing the DNA sequence. AMP-activated protein kinase (AMPK) is a master regulator of cellular energy homeostasis. It plays a crucial role in cancer by modulating key metabolic pathways, including autophagy, lipid biosynthesis, and glucose utilization. Emerging evidence suggests that AMPK is tightly regulated by epigenetic mechanisms, including DNA methylation, histone remodeling, and non-coding RNAs, which influence AMPK gene expression, activation, and post-translational stability. Non-coding RNAs, including long non-coding RNAs, microRNAs, and circular RNAs, often engage in dynamic feedback loops with AMPK, coupling metabolic stress to transcriptional and epigenetic remodeling. In parallel, DNA methylation and histone modifications influence AMPK signaling indirectly through modulation of upstream regulators and directly via chromatin-associated functions of AMPK. Despite extensive characterization of AMPK function in cancer metabolism, the epigenetic mechanism governing its regulation remain comparatively underexplored. Distinct epigenetic signatures associated with AMPK regulation are being explored as a potential therapeutic target. This review provides a comprehensive overview of epigenetic regulation of AMPK in cancer and highlights its potential in the context of metabolic reprogramming and precision oncology.

Cancer cachexia is a multifactorial syndrome marked by involuntary weight loss, skeletal muscle wasting, adipose tissue remodeling, and systemic metabolic dysfunction. Exosome-derived microRNAs (miRNAs) have emerged as key mediators, reprogramming host tissues and driving these hallmarks. However, no integrated framework has linked exosomal miRNAs to the proteomic and metabolomic alterations that characterize cachexia. This review critically synthesizes evidence on exosomal miRNAs in muscle atrophy, adipose browning, and systemic metabolic disruption. Tumor-secreted exosomal miRNAs activate proteolytic pathways (miR-21/29a via TLR7/8NF-κB/JNK), suppress antiapoptotic signals (miR-195a/125b targeting BCL-2), induce ER stress (miR-181a-3p), impair mitochondrial quality control (miR-122), and remodel metabolic signaling (miR-155, miR-183-5p). These mechanisms converge to produce proteomic signatures of enhanced proteolysis, apoptosis, and lipolysis, alongside metabolomic shifts toward amino acid efflux, fatty acid mobilization, and glycolytic inefficiency. This is the first integrated review linking exosomal miRNAs with proteomic and metabolomic signatures of cancer cachexia, offering a multiomics framework for biomarker discovery and therapeutic targeting. We highlight their potential as early biomarkers, therapeutic targets, and modulators of rehabilitation response, while outlining research gaps including limited clinical validation, intertumor heterogeneity, and the need for multiomics integration to advance translation into patient care.

Melanoma in adolescents and young adults (AYAs, 15-39 years) occupies a unique position between pediatric and adult disease. Although uncommon, it represents a meaningful proportion of malignancies in this age group. Its distinct epidemiology, histopathological subtypes, and clinical features necessitate age-specific approaches. This review synthesizes current evidence to clarify the unique characteristics of AYA melanoma and to inform future research and clinical practice.

Colorectal cancer is thought to develop through the stepwise accumulation of somatic mutations. Recent years have seen the publications of several studies greatly advancing our understanding of the molecular events driving the disease. However, individual studies tend to be small and additional insights may be obtained through the combination of data from multiple sources. We performed targeted sequencing of 2172 colorectal cancers from Icelandic patients and combined these data with publicly available mutation calls from 9 515 additional tumours collected from the literature. Analysing microsatellite stable (MSS) and instable (MSI) tumours separately, we find evidence of positive selection of mutations in 112 genes that replicate across multiple studies of patients with diverse demographics. We carried out a meta-analysis of conditional selection, identifying 57 gene pairs where a mutation in one gene influences the selection of the other. We describe many associations with tumour phenotypes, including a strong association between mucinous histology and mutations in the transcription growth factor beta (TGFb) pathway, only in MSS tumours. Our study demonstrates how combining evidence from multiple sources allows for new discoveries in cancer genomics.

Precision oncology relies on precision diagnostics, and histopathological diagnosis, along with biomarker evaluation, currently represents the cornerstone for personalized treatment. In gastrointestinal neoplasms, diagnostic assessment and molecular profiling are often performed on biopsy tissue, which may be quantitatively/qualitatively limited. Therefore, appropriate sample management is essential to avoid unnecessary waste and to obtain all the information necessary for treatment planning. Several factors may significantly impact biomarker testing: (i) pre-analytical issues; (ii) heterogeneity in biomarker expression; (iii) lack of standardization in biomarker testing and evaluation. Moreover, in the metastatic setting, inadequate/incomplete clinical information can lead to inappropriate sample handling, with negative implications. The application of appropriate guidelines in testing and reporting biomarker status according to clinical context is, therefore, strongly encouraged. In this position paper, the Italian Group of Gastrointestinal Pathologists (GIPAD), a section of the Italian Society of Pathological Anatomy and Cytology (SIAPeC-IAP), aims to summarize all the clinical and pathological requirements for adequate assessment of prognostic and predictive biomarkers in the gastrointestinal oncology patient, from biopsy acquisition to diagnostic reporting.

The nasal cavities and sinuses are the site of many tumoral entities, which are increasingly well described, especially since the advent of molecular biology. The present systematic review collates the current state of knowledge on six new entities described in the 2017 and 2022 versions of the WHO classification of sinonasal tumors: DEK::AFF2 rearranged squamous cell carcinoma, HPV-associated multiphenotypic sinonasal carcinoma, NUT carcinoma, SMARCB1-deficient and SMARCA4-deficient carcinoma, biphenotypic sinonasal sarcoma, and adamantinoma-like Ewing sarcoma. A systematic literature search was performed on PubMed. The inclusion criteria focused on English-language articles precisely describing the histologic, immunohistochemical, molecular, clinical and prognostic characteristics of these entities. It is essential to be able to identify these entities, as they have distinct profiles in terms of progression and prognosis compared to other sinonasal tumors. The present study exhaustively describes their clinical and pathologic characteristics.

The epidermal growth factor receptor (EGFR) mutation represents one of the most prevalent driver gene alterations in non-small cell lung cancer (NSCLC) patients. EGFR tyrosine kinase inhibitors (EGFR-TKIs), particularly third-generation agents, have emerged as the top priority for patients harboring activating mutations. This review commences with a concise introduction to the EGFR-mutated tumor microenvironment and its dynamic changes associated with EGFR-TKI administration. We systematically summarize current therapeutic options for patients who progress on EGFR-TKIs, providing an overview of immunotherapy resistance mechanisms and corresponding management strategies. Finally, this review discusses the progression patterns and subsequent therapies in patients pretreated with EGFR-TKIs who develop resistance to immunotherapy. A treatment algorithm structured around resistance typology, molecular profiling, and progression patterns provides substantial clinical value for guiding therapeutic decisions in this patient population.

Circulating tumor DNA (ctDNA)-based liquid-biopsy has emerged as a transformative tool in breast cancer management, offering non-invasive, real-time insights across the clinical continuum. By capturing tumor-specific genetic and epigenetic alterations-such as mutations, copy number variations, and methylation patterns-ctDNA enables applications in early screening, evaluation of treatment response, minimal residual disease monitoring, and tracking of resistance mechanisms. Technological advances in PCR-based methods, next-generation sequencing, and biosensor-based profiling have significantly enhanced detection sensitivity and specificity, supporting personalized therapeutic guidance and dynamic adaptation of treatment strategies. However, clinical implementation faces challenges related to assay standardization, variable detection sensitivity, high costs, and limited large-scale prospective validation. Future efforts should focus on technological refinement, multi-omics integration, and evidence generation through large-scale multicenter clinical trials to position ctDNA as a cornerstone of precision oncology in breast cancer.

Mantle cell lymphoma (MCL) is a rare, aggressive form of non-Hodgkin lymphoma that arises from cells within the mantle zone (the outer ring of lymphocytes surrounding the center of a lymphatic nodule). Recent treatment advances, such as the introduction of Bruton tyrosine kinase inhibitors and chimeric antigen receptor T-cell therapies, have improved outcomes for many patients. Development of resistance is common, though, and relapse rates are high in MCL. The molecular mechanisms that contribute to resistance remain unclear, and the clinical heterogeneity of MCL can make it difficult to predict how patients will respond to treatment. Thus, there remains an urgent need for continued research on the molecular drivers of MCL pathogenesis, mechanisms of resistance, and novel strategies for targeting these pathways to improve outcomes for patients across the spectrum of disease. In April 2025, researchers gathered for the Lymphoma Research Foundation's 21st Mantle Cell Lymphoma Scientific Consortium and Workshop to discuss recent developments in the characterization and treatment of MCL. This report, which includes a summary of each presentation, aims to review the findings presented at the workshop and highlight new opportunities and unanswered questions in the care of patients with MCL, paving the way for novel treatments to improve outcomes and experiences in the years to come.

Metastatic invasiveness emerges from coordinated intrinsic programs and microenvironmental cues that converge on mitochondrial quality control (MQC). Here, we use "context" to denote stage- and site-aware constellations of tumor-intrinsic states (e.g., mtROS tone, mtDNA integrity, epigenetic wiring, cellular stiffness, oncogenic mutations) and extrinsic landscapes (oxygen-nutrient availability, ECM mechanics, stromal/inflammatory signals). These axes jointly shape mitochondrial adaptation by tuning bioenergetics, redox balance, metabolic plasticity, fission-fusion dynamics, mechanosensitive hubs, and Ca2+ homeostasis. As pressures intensify, mitochondrial vulnerabilities-such as mtDNA compromise and mtUPR activation-signal the engagement of mitophagy to preserve organelle fitness under stress. Through these coupled changes in mitochondrial performance and stress responses, context governs EMT/MET plasticity and transitions across migratory, invasive, and proliferative states. Mechanistically, ubiquitin conjugation, via E3 ligases and deubiquitinases, serves as an integrating conduit that links mitochondrial remodeling and mitophagy to cytoskeletal reprogramming and invasive behavior. This ubiquitin-mitochondria interface therefore represents a coherent therapeutic entry point; translational strategies including PROTAC-enabled targeting and selective E3/DUB or mitophagy-pathway modulators may rebalance pathological ubiquitin signaling, restore mitochondrial homeostasis, and constrain tumor dissemination.

Breast cancer is a complex disease which has many factors affecting its progression and metastasis. Although steroid hormones, especially oestrogen, are most commonly associated with breast cancer, growth hormone (GH) also plays a substantial role in its development and spread via the activation of downstream signalling pathways and the regulation of growth factors such as insulin-like growth factor-1 (IGF-1) and the vascular endothelial growth factor (VEGF). Breast cancer patients usually have elevated levels of GH and IGF-1 in their circulation. Growth hormone receptor (GHR) signalling enhances migratory ability of tumour cells and excess IGF-1 production promotes angiogenesis. Gaining a full understanding of the mechanisms behind GH and breast cancer will allow researchers to develop more therapeutics to treat this devastating disease.