Epithelial-mesenchymal transition (EMT) plays a critical role in tumor progression; however, the underlying molecular mechanisms of EMT in papillary thyroid carcinoma (PTC) remain incompletely understood. This study aimed to investigate EMT-related mechanisms in PTC using an integrative approach combining single-cell RNA sequencing and machine learning.

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.

Cancer is the leading cause of death worldwide. This study evaluated the anti-liver cancer influence of the unsaponifiable fraction (UnSap) derived from black Vitis vinifera seed oil (BVVO) using the HepG-2 cell line and a HCC mouse model. Compared with 5-fluorouracil (5-FU), UnSap exhibited a strong antioxidant capacity, excellent safety (in PBMCs), and a higher selectivity index (SI) with a lower IC₅₀ against HepG-2 cells. It effectively induced apoptosis and modulated the expression of key genes involved in cell cycle progression. The docking results predicted that the abundant constituents of UnSap can interfere with the interaction between β-catenin and human T-cell factor-4 (HTCF-4) and may inhibit the activity of key regulatory proteins involved in HCC proliferation and stemness. In HCC-bearing mice, UnSap significantly improved the expression of serum liver function markers (0.4-1.3-fold), restored redox balance (> threefold), and preserved hepatic tissue architecture. It also modulated the expression of critical genes associated with apoptosis (> 20-fold), cell cycle regulation (> fourfold), inflammation (> fivefold), angiogenesis (threefold), and cancer stemness (> 45-fold). These therapeutic effects are likely attributed to its high phenolic and phytosterol content, as confirmed by HPLC analysis. Across all investigated parameters, UnSap demonstrated superior anticancer efficacy compared with 5-FU. These findings highlight the potential of UnSap as a promising natural therapeutic candidate and provide a foundation for future studies on its bioactive constituents for the development of novel anticancer agents.

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.

Objective: To assess the utility of histopathological and immunohistochemical characteristics in identifying POLE-mutated (POLEmut) endometrial carcinoma (EC). Methods: A total of 1 541 EC cases that underwent molecular classification at Peking University Third Hospital from January 2018 to December 2024 were included. Cases were categorized into POLEmut and non-POLEmut groups (including p53-abnormal, mismatch repair-deficient, and no specific molecular profile subtypes). A comparative analysis of histopathological features, mismatch repair (MMR) protein expression, and p53 immunostaining patterns was performed. A multivariable logistic regression-derived prediction model for POLEmut status was developed and internally validated. Results: POLEmut tumors showed significantly higher frequencies of prominent peritumoral lymphocytes (PTLs) and tumor-infiltrating lymphocytes (TILs), high-grade nuclei, bizarre nuclei, clear cytoplasm, and ambiguous morphology compared with non-POLEmut tumors (all P<0.05). Multivariable analysis identified severe PTLs/TILs infiltration, high-grade nuclei, ambiguous morphology, and clear cytoplasm as independent positive correlates for POLE mutation status, while aberrant p53 expression and MMR protein loss were negative correlates. The scoring system showed robust discrimination, with an area under the curve (AUC) of 0.867 in the training set (n=1 319) and 0.873 in the test set (n=222). At the ≥3- point cutoff, it provided a sensitivity of 80.8%, specificity of 66.3%, and negative predictive value (NPV) of 96.3% in the test set. Calibration analysis indicated good overall performance (Brier score=0.045), though local miscalibration was observed in intermediate-and low-risk subgroups. Conclusions: This POLEmut scoring system achieves high sensitivity and high NPV for initial screening of POLEmut EC. Despite a relatively low positive predictive value requiring confirmatory sequencing, it effectively enriches candidates needing POLE gene sequencing in resource-limited settings. Future multicenter validation is warranted to assess its clinical utility.

Objective: To study the clinicopathological features and key differential diagnosis of clear cell adenocarcinoma (CCA) of the urinary tract. Methods: A retrospective analysis was performed on the clinicopathological data, immunophenotypes, and molecular test results of patients with pathologically confirmed primary CCA of the urinary tract at Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China from December 2015 to September 2024. This study was supplemented by a review of the relevant literature. Results: Nine patients were included (1 male and 8 females), age 57.0 (44.5, 61.0) years old. The main symptoms were urinary tract irritation and hematuria. Th lesions were in the urethra of 5 patients and in the bladder in 4 patients. Macroscopically, the tumors were cauliflower-like, with edema and firm consistency. Microscopically, they showed mostly papillary/tubular-cystic structures, with solid sheet-like arrangements. The tumor cells showed clear or eosinophilic cytoplasm, moderate to high nuclear grade, prominent nucleoli, and frequent mitotic figures. The tumor cells also exhibited strong expression of PAX8, CK7, and HNF1-β, various positivity of Napsin A and P504s, and partial expression of SOX17, CK20, and GATA3. The Ki-67 index ranged from 30% to 70%, and p53 showed a heterogeneous expression pattern. The cells were negative for p63 and the renal cell carcinoma marker (RCC). Among the 7 cases subject to urine fluorescence in situ hybridization (FISH) testing, 5 cases showed abnormal centromeric signals. One case underwent next-generation sequencing (DNA-seq) and harbored a nonsense ARID1A mutation. Two patients underwent radical surgery, 3 total urethrectomy, and 4 palliative surgery. Four patients received postoperative chemotherapy. The follow-up ranged from 9 to 58 months: 3 patients had tumor recurrence while 2 died. Conclusions: CCA of the urinary tract is a rare and aggressive malignancy. Its histological morphology resembles that of ovarian CCA. The diagnosis should be based on a combination of morphological features and immunophenotype. It is recommended to use PAX8, CK7, HNF1-β, and Napsin A as a core immunohistochemical panel, while testing SOX17 can also help.

Objective: To study the clinicopathological features, immunophenotype, diagnosis, and prognosis of TSC/mTOR mutation-associated renal cell carcinoma with leiomyomatous stroma (M/TSC-RCC-LMS). Methods: Nine cases of molecularly confirmed M/TSC-RCC-LMS were collected at the Affiliated Hospital of Qingdao University (7 cases) and No. 971 Hospital of the People's Liberation Army, Qingdao, China (2 cases) between December 2011 and August 2024. Histological evaluation, immunohistochemical staining, and molecular analysis were performed, along with literature review. Results: Among the 9 patients, 1 was male and 8 were female, with their ages 48(35,55) years. Eight cases were detected during routine physical examinations, while 1 case presented with painless gross hematuria. All 9 cases were located within the renal parenchyma, presenting nodular masses with tumor diameters 2.0(1.4,2/7) cm. The lesions were well-circumscribed. The tumors were solid, grayish-white, grayish-yellow or grayish-red in color, and soft in consistency, while one case showed cystic-solid characteristics. All 9 cases exhibited thick fibromuscular pseudocapsules. In 8 cases, smooth muscle components within the capsule were observed extending into the tumor, dividing the neoplastic tissue into nodular and clustered patterns. The tumor cells were primarily arranged in tortuous, elongated branching tubular structures, with focal areas showing small amounts of delicate papillary structures containing fibrovascular cores. They also had abundant cytoplasm that was pale-staining or mildly eosinophilic, occasionally clear. The nuclei were round or irregular in shape, with some showing conspicuous nucleoli. All the 9 cases showed patchy to diffusely strong expression of CK7 (70%-100%). Carbonic anhydrase Ⅸ (CAⅨ, 6/9) and CD10 (membranous positivity, 8/9) demonstrated variable extent and intensity of expression. Glycoprotein nonmetastatic melanoma protein B (GPNMB) showed diffusely moderate to strong positivity in 7 of the 9 cases. The 9 cases were all negative for α-methylacyl-CoA racemase (AMACR), TFE3, TFEB, TCEB1, HMB45, and Melan A, with Ki-67 proliferative index ranging from 1% to 10%. Whole exome sequencing revealed mTOR gene mutations in 5 cases, concurrent TSC2 and mTOR mutations in 1 case, a TSC2 mutation in 1 case, and germline TSC1 mutations in 2 cases. Follow-up of the cases ranged from 6 to 159 months. All patients were alive at the end of the follow-up, with no recurrence or metastasis. Conclusions: M/TSC-RCC-LMS exhibits unique morphological and immunophenotypic characteristics. The tumor cells exhibit abundant pale or mildly eosinophilic cytoplasm, forming elongated, tortuous branching tubules accompanied by stromal smooth muscle components. These are typically morphological features of this renal cell carcinoma subtype. The contribute to the diagnosis and differential diagnosis of the tumor diffusely strong positivity of CK7 and the positivity of GPNMB. This type of renal cell carcinoma often demonstrates indolent biological behaviors with favorable prognosis and is expected to be newly classified as an independent subtype of renal cell carcinoma.

Objective: To explore the clinicopathological features, immunophenotype, molecular characteristics, and prognosis of primary malignant solitary fibrous tumor (MSFT) of the kidney. Methods: The clinicopathological data of four renal MSFT cases diagnosed at the Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China and one case at the Ningbo Clinical Pathology Diagnostic Center, Ningbo, China between 2015 and 2025 were collected. The clinical features, histomorphology, and immunohistochemical characteristics were analyzed. Fluorescence in situ hybridization (FISH) and RNA-based next-generation sequencing were performed. Follow-up and review of relevant literature were conducted. Results: Among the five patients, three were male and two were female, aged 70(61,71) years. The tumors were all found during routine physical examinations. Four cases (cases 1, 3, 4, and 5) occurred in the left kidney, and one case (case 2) first occurred in the left kidney and recurred in the right kidney 5 years later. Four cases had a single lesion with a maximum diameter of 6.0-19.0 cm, and one case (case 5) had 2 lesions with maximum diameters of 2.0 cm and 4.0 cm, respectively. Histologically, three cases (cases 1, 2, and 5) were de novo MSFT, one case (case 5) was morphologically similar to synovial sarcoma with spindle cells arranged densely in bundles, one case (case 1) had sheets of epithelioid tumor cells, and one case (case 2) had alternating myxoid and spindle cell areas, with sparse tumor cells in the myxoid areas and dense tumor cells in the spindle cell areas. Two cases (cases 3 and 4) were classic solitary fibrous tumor (SFT) with dedifferentiation, and the dedifferentiated components were high-grade undifferentiated sarcoma. In the typical SFT areas, tumor cells were alternately dense and sparse, with collagenized areas and rare mitotic figures, while branching or hemangiopericytoma-like structures were also present. In the dedifferentiated areas, tumor cells were spindle-shaped or epithelioid with conspicuous nucleoli. Necrosis was seen in all three de novo MSFT cases (cases 1, 2, and 5) and one dedifferentiated case (case 4). The mitotic figures in three de novo SFT cases and two dedifferentiated areas were 4 to 10 per 10 HPF. No heterologous differentiation was found in any of the five cases. According to the Demicco risk classification, four cases were of moderate risk, and one case (case 4) was of high risk. Four cases showed diffuse expression of STAT6, while one case (case 3) showed partial expression. CD34 was diffusely positive in 3 cases, partially positive in one case (case 4) and negative in one case (case 1). Only one of the 5 cases expressed CKpan which was focally positive. PAX8, desmin, BCOR, S-100 protein, Melan A and HMB45 were all negative. H3k27Me3 expression was retained. FISH showed no SYT (SS18, 18q11) rearrangements in two cases (cases 4 and 5), and no MDM2 amplification in one case (case 5). RNA sequencing in four cases detected NAB2::STAT6 gene fusion, all of which were NAB2ex6::STAT6ex16 fusion subtypes. Follow-up data were available for four cases, with the follow-up period of 11-30 months. Among the 4 cases, one case had liver metastasis 3 months after surgery, and one case of left renal MSFT (moderate risk) had right renal recurrence 5 years after surgery. The other two had no recurrence or metastasis. Conclusions: Renal MSFT with moderate to high-risk is rare, shows a wide morphological spectrum and needs to be differentiated from various tumors. Extensive sampling, careful morphological observation, immunohistochemical staining and molecular detection of NAB2::STAT6 fusion are helpful for the diagnosis. It appears to have aggressive biological behaviors.

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.

In this study, Wisnovsky and colleagues1 investigate the genetic determinants underlying cancer-associated glycome remodeling. Using genome-wide CRISPR-based approaches, they identified regulators of cell surface glycosylation. Specifically, genetic networks are discovered that upregulate cancer-related ligands of the sialic acid-binding immunomodulatory Siglecs.

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

To comprehensively characterize the clinical and genomic landscapes of PIK3CA, AKT1, and PTEN alterations and examine their functional and therapeutic implications in AKT-driven breast cancer.