Glioblastoma (GB), defined as IDH-wildtype CNS WHO grade 4 tumour according to the 2021 WHO classification of CNS tumours, remains a uniformly lethal malignancy in which the efficacy of temozolomide (TMZ) continues to be constrained by both intrinsic tumur biology and the pharmacological barrier imposed by the blood-brain barrier (BBB). Given the central role of the ABCB1 (MDR1/P-glycoprotein) efflux transporter in regulating CNS drug disposition, germline variation in ABCB1 has been proposed as a potential determinant of interindividual variability in TMZ response. This systematic review synthesised clinical evidence from four independent studies, encompassing more than 400 GB patients, evaluating the association between ABCB1 polymorphisms and TMZ efficacy and patients' survival. Across the available literature, the influence of ABCB1 genetic variation emerged as limited and inconsistent. An early study reported a marked survival advantage for carriers of the ABCB1 C1236T C/C genotype treated with TMZ, suggesting reduced efflux and enhanced drug exposure. However, subsequent investigations, including epigenetic analyses, high-quality multivariate survival modelling and a pharmacokinetic study demonstrating genotype-dependent differences in plasma TMZ concentrations, did not replicate a corresponding survival effect. Across the remaining cohorts, common variants such as 1236C>T, 2677G>T/A, 3435C>T and 1199G>A showed no robust association with clinical outcome, indicating that transporter-mediated modulation is likely overshadowed by dominant prognostic drivers, including MGMT methylation, IDH status and tumour heterogeneity. Collectively, current evidence does not support ABCB1 polymorphisms as reliable predictive biomarkers of TMZ response in GB. Nonetheless, the pharmacokinetic signals observed, together with emerging technologies capable of selectively modulating efflux activity at the tumour-BBB interface, point to a continued role for ABCB1 in future therapeutic strategies. Integration of transporter genomics with spatial pharmacokinetics and molecular stratification will be essential to refine drug delivery and improve outcomes in GB.

Desmoplastic small round cell tumor (DSRCT) is an ultra-rare sarcoma with limited treatment options. Here, we show that comprehensive molecular profiling informs diagnosis and individualized therapy in this disease. We report the results of whole-genome/exome, transcriptome, and DNA methylome analyses performed in 30 refractory DSRCT patients, complemented by (phospho)proteomic profiling in nine, within a nationwide precision oncology program. In eight patients (27%), DSRCT was diagnosed only after molecular profiling. Although DSRCTs have "quiet" genomes, 28 patients (93%) received 107 molecular-based management recommendations, including assessment of clinical trial eligibility in 17 (57%). Most recommendations are informed by overexpression of tyrosine kinases, SSTR3/5, and CLDN6, detected in 45%, 33%, and 20% of cases, respectively. Thirteen patients (46%) received recommended therapies, yielding disease control in eight (62%), including three long-lasting responses to pazopanib and trastuzumab deruxtecan, the latter administered based on ERBB2 overexpression in the absence of aberrant ERBB2 kinase activation. These findings demonstrate that multi-omics profiling provides clinically actionable insights for DSRCT management.

ObjectiveOral squamous cell carcinoma is the most common malignant tumor occurring in the head and neck region. Current treatment principles are based on radical surgery, supplemented by radiotherapy and chemotherapy. However, the 5-year survival rate for patients remains approximately 50%. Therefore, further research into the molecular mechanisms underlying oral squamous cell carcinoma development is needed to identify more effective treatment methods.MethodsIn this study, immunohistochemical techniques were used to quantitatively analyze the expression levels of E-cadherin, vimentin, CD206, programmed cell death receptor 1 (PD-1), and programmed cell death ligand 1 (PD-L1) in 45 pathological sections of oral squamous cell carcinoma. The results showed that the expression levels of vimentin, CD206, and programmed cell death ligand 1 were significantly associated with overall survival. Additionally, Cox multivariate analysis indicated that the M2 macrophage marker, CD206, is an independent risk factor for poor prognosis in oral squamous cell carcinoma. Furthermore, correlation analysis revealed that E-cadherin expression was negatively correlated with vimentin, CD206, and programmed cell death ligand 1 expression levels. Vimentin expression was positively correlated with programmed cell death receptor 1 and programmed cell death ligand 1 expressions.ResultsImmunohistochemical examination indicated that M2 macrophages are an independent risk factor for poor prognosis in oral squamous cell carcinoma and are closely associated with overall survival. Furthermore, they may influence the development and progression of oral squamous cell carcinoma tumors by inducing epithelial-mesenchymal transition in oral squamous cell carcinoma tumor cells. Third, programmed cell death ligand 1 expression has an adverse impact on oral squamous cell carcinoma prognosis and is significantly correlated with the expression levels of CD206, E-cadherin, and vimentin.ConclusionsThis study indicates that programmed cell death receptor 1/programmed cell death ligand 1 and CD206 expressions are independent risk factors for poor oral squamous cell carcinoma prognosis; however, whether programmed cell death receptor 1/programmed cell death ligand 1 expression influences the occurrence and development of oral squamous cell carcinoma through M2 macrophages requires further investigation.

Tumors foster an immunosuppressive microenvironment to evade the antitumor immune response. However, the influence of intratumoral immunosuppressive steroids on tumor-infiltrating natural killer (NK) cells and their implications for effective immunotherapy has remained largely unexplored. Here, we report that the functional enrichment of glucocorticoid cortisol signaling in the lung tumor microenvironment (TME) impairs NK cell anti-tumor cytotoxicity and exacerbates hypoxic stress. Cancer-associated fibroblasts (CAFs) and macrophages convert inactive cortisone to active cortisol, while T cells, fibroblasts, myeloid cells, macrophages, and cancer cells contribute to de novo steroid biosynthesis, collectively establishing a steroid-rich niche. Pharmacological inhibition of the glucocorticoid receptor (GR) in vivo alleviates cortisol-mediated immune suppression, resulting in reduced tumor growth and enhanced cytotoxicity of tumor-infiltrating NK cells. To overcome the cortisol-induced dysfunction of solid tumor targeting immunotherapy, we engineered chimeric antigen receptor (CAR) -NK cells specific to the Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) (highly expressed in lung tumors) and rendered them cortisol-resistant by genetic deletion of the cortisol receptor gene NR3C1. In cortisol-rich niches, cortisol-resistant CAR-NK cells sustained antitumor cytotoxicity. Mechanistically, NR3C1 deletion relieved cortisol-mediated suppression of PI3K-AKT-NF-κB signaling, restored anti-tumor activity, and markedly reduced hypoxic stress. In lung metastasis models, cortisol-resistant CAR-NK cells achieved superior tumor control and significantly reduced tumor burden compared with conventional CAR-NK cells. Together, these findings identify local cortisol signaling as a critical barrier to solid tumor immunotherapy and establish cortisol-resistant CAR-NK cells as a promising strategy for targeting steroidogenic solid tumors, which can be combined with therapeutic glucocorticoids.

Human solid tumors such as hepatocellular carcinomas (HCC) establish a complex immunosuppressive tumor microenvironment (TME) that undermines the efficacy of existing immunotherapies such as chimeric antigen receptor T (CAR T) cell therapy. To advance immunotherapy for HCC, it is crucial to delineate the molecular mechanisms that drive TME formation and immune evasion.

Aim: Validate the association RAD18 Arg302Gln (rs373572) and OGG1 Ser326Cys (rs1052133) - with Renal Cell Carcinoma (RCC) susceptibility and histopathological characterization.

The incidence of hepatocellular carcinoma (HCC) is increasing each year, with challenges such as increasing drug resistance and a high post-treatment recurrence rate. Therefore, investigating the novel pathogenic mechanisms is warranted. In this study, we investigated novel molecular mechanisms that affect HCC progression. Immunofluorescence analysis, immunohistochemical staining, and immunoblotting were performed to assess elevated IGF-1R expression in HCC cells. The EdU incorporation and colony formation assays revealed that IGF-1R promotes HCC cell proliferation. Furthermore, wound healing and Transwell migration assays revealed that IGF-1R phosphorylation enhances the migration of HCC cells. In addition, JC-1 apoptosis assays revealed that IGF-1R inhibits HCC cell apoptosis. Immunoblotting was performed to assess the protein phosphorylation level of Akt/GSK-3β downstream of IGF1/IGF-1R to explore the molecular mechanism. IGF-1R expression was significantly increased in HCC cells, and ligand-induced phosphorylation promoted HCC cell proliferation and migration and inhibited apoptosis. Additional studies revealed that the activation of IGF-1R phosphorylation promotes epithelial-mesenchymal transition in HCC cells by increasing the phosphorylation levels of Akt and GSK-3β. Collectively, our study findings suggest that IGF-1/IGF-1R promotes HCC progression by activating the Akt/GSK-3β pathway.

M2-like macrophages play a critical role in breast cancer progression. Although JMJD3 is reported to play a significant role in M2-like macrophage polarization, its precise mechanism remains unclear. By using PMA, IL-4, and IL-13, we successfully induced THP-1 cells into M2-like macrophages, which subsequently promoted breast cancer cell proliferation and inhibited apoptosis, accompanied by increased JMJD3 expression. We demonstrated that JMJD3 enhances M2-like macrophage polarization: knockdown of JMJD3 decreased the M2-like macrophage gene expression, while overexpression of JMJD3 produced the opposite effects. Furthermore, JMJD3 promoted M2-like macrophage polarization through the STAT6/IRF4 axis. Knockdown of JMJD3 abrogated IL-4/IL-13 induced IRF4 expression, while overexpression of JMJD3 upregulated IRF4 expression. Inhibition of STAT6 downregulated the expression of JMJD3, IRF4, and M2-like macrophage marker genes. Additionally, inhibiting JMJD3 and STAT6 in macrophages increased cell apoptosis and decreased cell viability in breast cancer cells, while JMJD3 overexpression exhibited pro-tumor activity. In conclusion, our findings highlight the role of JMJD3 in regulating M2-like macrophage polarization and its impact on breast cancer development through the STAT6/IRF4 axis.

We aimed to analyze the correlation between radiomic features of pulmonary invasive mucinous adenocarcinoma (PIMA), abnormal expression of the FoxM1 and Sox9 genes, and pathological characteristics of the tumor.

Integrating spatial omics with artificial intelligence is likely to advance biomarker research and diagnostics, with the potential to pair mechanistic insight into spatial target biology. By developing scalable, reproducible quantification in routine pathology, it can help bridge discovery, validation, and real-world clinical implementation.

Copyright: © 2026 Adeyika et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Aberrant DNA methylation changes lead to abnormal gene expression that contributes to the development and progression of prostate cancer (PCa). Inquiry of genome-wide DNA methylation dataset, we identified the homeodomain pancreatic and duodenal homeobox 1 (PDX1) gene as differentially hypermethylated in PCa compared to normal prostate tissues. Immunohistochemical analysis of matched PCa and normal prostate tissues using tissue microarray showed a significant 2.33-fold (p = 0.0001) higher PDX1 protein expression in the PCa compared to the normal prostate tissues. In PCa cell lines (PC-3 and LNCaP) engineered to stably overexpress or knockdown PDX1, the ectopic PDX1 expression significantly enhanced cell proliferation and migration, whereas PDX1 knockdown suppressed these phenotypic processes. Quantitative RT-PCR and Western blot analysis demonstrated that PDX1 overexpression was associated with increased expression of key metabolic regulators; INSR, IGF1R, CXCR4, CDH2, TWIST1, and SNAI1, whereas there is decreased expression of ESR2, and TNFα. Conversely, PDX1 knockdown led to the opposite effect in expression profiles of these metabolites. Notably, these effects were more pronounced under high-glucose conditions compared to low-glucose environments. Overall, our findings suggest that PDX1 plays a tumor-promoting role in human PCa cells by influencing expression of metabolites in insulin, inflammatory, and epithelial-mesenchymal transition (EMT) signaling pathways. Given its potential role in metabolic regulation, full insights into the function of PDX1 in PCa could contribute to improved treatment and prevention strategies, particularly for men with PCa and comorbidities such as obesity and diabetes.

Copyright: © 2026 Ahmed and Núñez-Ríos. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Burgeoning technological and clinical advances have significantly reshaped glioma classification. To assess the evolution of these changes, we analyzed bibliometric data from Web of Science to explore patterns in the socio-clinical domains of glioma classification research. Using network analysis, we built a direct citation network linking articles to authors, focusing on citations. Main Path Analysis provided an overview of research evolution, Key Route Analysis identified influential papers, and K-core analysis revealed densely connected articles. The network comprised 46,204 nodes and 231,432 arcs, highlighting DNA methylation profiling’s role in advancing molecular biomarker-based classification models. KRA emphasized advanced imaging and molecular techniques as key drivers, while K-core analysis identified articles cited at least 19 times. The findings indicate that the subset of articles focusing on glioma classification that incorporate social factors is relatively scarce in the analyzed data, in contrast to the prominence of epigenetic and imaging factors in the literature. Unlike previous studies that focused primarily on metrics such as the h-index, our approach identifies the limited but notable mention of social factors in glioma classification research, thereby highlighting a thematic gap. Through quantitative network analysis complemented by narrative interpretation, we uncovered patterns and substructures that offer deep insights into the evolving research landscape.

Copyright: © 2026 Makovec et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Prostate gland cells can be transcriptionally and morphologically characterized as basal and luminal. About 30–40% of advanced prostate cancers (PC) harbor basal-like transcription programs. In castration-resistant PC (CRPC), studies indicate that basal and stem cell-like (SCL) tumors are major resistance mechanisms to androgen receptor (AR)-targeted therapies. SCL tumors have reduced AR activity and increased stem-cell activity that promotes tumor formation, which contributes to poor clinical outcomes. We determined that CREB5 is a key regulator of basal and SCL transcriptional programs and tumor-forming phenotypes in PC. Through in silico modeling of PC transcriptomes and several pre-defined PC signaling programs, CREB5 expression was best associated with basal-like gene signatures and SCL-associated genes in primary PC and CRPCs (n = 493 and 208). This included associations with FOSL1 and other AP-1 transcription factors. We further found that CREB5 interacted with AP-1 proteins and bound to the regulatory elements of AP-1 genes, suggesting a mechanistic role in regulating the activity of AP-1 genes. In AR-positive cells, CREB5 overexpression promoted cell colony growth with tumorigenic properties and increased tumor size in vivo. These findings implicate CREB5 as a driver of the transcriptional programs underlying AR-independent basal and SCL CRPC subtypes, and this activity is detectable in primary PC.

Lung cancer is the third most common malignancy in Iceland and remains the leading cause of cancer-related mortality. Lung cancer may harbor driver mutations affecting the function of Epidermal growth factor receptor (EGFR), Anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1 (ROS1), B-raf proto-oncogene (BRAF), RET proto-oncogene (RET), MET proto-oncogene (MET), and NTRK, which can influence the selection of targeted therapies and treatment outcomes. In Iceland, EGFR testing was initiated in 2005, and in 2016, multigene targeted panel became standard for tumor testing. The objective was to determine the uptake of testing and frequency of targeted mutations in lung cancer nationwide, the utilization of targeted therapies, and duration of such treatments.

Primary mesenchymal tumors of the meninges include various types, with meningioma being the most prevalent. Non-meningothelial primary tumors of the meninges are uncommon and present diagnostic difficulties due to their potential morphological similarities with each other and with the anaplastic subtype of meningioma. Intracranial dedifferentiated chondrosarcoma is extremely rare and is defined by the presence of both a conventional chondrosarcoma component and a non-cartilaginous sarcoma component. Diagnosing this tumor can be particularly challenging in biopsy samples or when the chondrosarcoma component is not prominently represented. We report a rare case of dedifferentiated chondrosarcoma of the cavernous sinus in a specimen containing only the dedifferentiated component and exhibiting an IDH1 mutation, underscoring the importance of genetic characterization for the differential diagnosis of tumors in this anatomical region. Given the recent evidence supporting the efficacy of IDH inhibitors in chondrosarcomas, identifying mutations in these genes may also have significant therapeutic implications.

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults, characterized by distinct histopathological and molecular features and often associated with poor prognosis due to its high metastatic potential. While histology, BAP1 status, and chromosomal changes are established prognostic markers, integration of morphological, immunophenotypic, and molecular data is evolving.

Thymic carcinomas (TC) are rare and understudied tumors. Pitfalls exist with TC diagnosis, and biomarkers are needed to support the pathologist. Here, we tested a series of biomarkers to differentiate TC from type B3 thymoma.

The management of hormone receptor-positive/HER2-negative (HR+/HER2-) metastatic breast cancer (MBC) relies on molecular testing to inform treatment decisions. PIK3CA mutations, present in ~40% of cases, represent a key predictive biomarker for PI3K-pathway-targeted therapies. Despite its clinical relevance, PIK3CA testing continues to face challenges related to laboratory organization, standardization, and access. We conducted a nationwide, cross-sectional survey to evaluate current practices and institutional readiness for PIK3CA testing in Italy, in the context of the anticipated expansion of PI3K-targeted therapies, including inavolisib. A total of 118 healthcare professionals from institutions across 15 regions participated, providing data on test availability, laboratory workflows, analytical methodologies, accreditation status, and implementation barriers. Descriptive statistics were used for analysis. Overall, 88.1% of institutions reported the ability to perform PIK3CA testing, with 57.6% offering on-site analysis. Testing was predominantly performed in pathology laboratories (76.5%), followed by molecular biology (16.2%) and genetics laboratories (7.4%). However, 46.6% of institutions lacked formal molecular accreditation, and ISO:15189 certification remained uncommon. Pre-analytical workflows relied mainly on formalin-fixed paraffin-embedded (FFPE) tissue samples (89.7%), with limited routine use of liquid biopsy. Next-generation sequencing (NGS) was the most frequently adopted analytical approach (45.6%), followed by combined NGS and PCR-based strategies (36.8%). Most institutions reported turnaround times of 7-15 days. In conclusion, this updated survey indicates progress in access to PIK3CA testing and consolidation of NGS-based methodologies in Italy. Nevertheless, persistent gaps in accreditation, heterogeneous workflows, and limited integration of liquid biopsy highlight ongoing challenges in standardization and diagnostic equity. Coordinated national strategies will be essential to ensure consistent, high-quality molecular diagnostics in HR+/HER2- MBC.

Alterations in the phosphoinositide 3-kinase (PI3K)/AKT/PTEN signaling pathway are a well-recognized mechanism of resistance in hormone receptor-positive, HER2-negative metastatic breast cancer (HR+/HER2- mBC). These alterations are present in approximately half of patients with HR+/HER2- mBC. The major alterations in the pathway are somatic mutations in the PIK3CA (40-45%) and AKT1 (5%) genes, and loss-of-function alterations in PTEN (5-10%). New targeted agents that act against these alterations have been developed. Therefore, it is important to determine the mutational status of genes in this pathway to potentially offer a therapeutic alternative for these patients. In this review, we discuss the clinical and biological significance of PI3K pathway alterations in HR+/HER2- mBC, focusing on tumors that progress following endocrine therapy and CDK4/6 inhibitor treatment. We then highlight how different diagnostic strategies, including sample type, testing methodology, and timing, can improve the identification of patients who are eligible for targeted therapies and promote the effective integration of molecular diagnostics into routine clinical care.

Polycystic ovary syndrome (PCOS) is one of the most prevalent and heterogeneous disorders in reproductive endocrinology, contributing to substantial reproductive, metabolic, and psychological morbidity. Despite major advances in genomics, neuroendocrinology, and systems biology, translation into disease-modifying therapies remains limited. This Perspective argues for a strategic shift toward precision medicine, supported by molecular subtyping, multi-omics profiling, and artificial intelligence (AI). These tools now enable biologically informed patient stratification and the identification of novel therapeutic targets. We highlight emerging strategies - including anti-Müllerian hormone (AMH) neutralization, neuroendocrine modulators, metabolic agents, and next-generation biologics - and discuss the regulatory, ethical, and operational considerations required to accelerate innovation. A coordinated, multi-disciplinary approach integrating computational analytics, biomarker-driven endpoints, and patient-centered outcomes is essential to close the longstanding gap between scientific potential and clinical reality.