Search Results (787)

Clear cell renal cell carcinoma (ccRCC), hepatocellular carcinoma (HCC), lung adenocarcinoma (LUAD), and pancreatic ductal adenocarcinoma (PDAC) are highly lethal cancers that share molecular mechanisms underlying tumor progression, yet common biomarkers across these cancers remain largely unexplored. Microarray datasets for the four cancers were analyzed to identify differentially expressed genes (DEGs) using adjusted $p<0.05$ and $\left|{\log }_2\mathrm{FC}\right|>1$ as significance thresholds. Disease-associated gene targets were collected from CTD, DISEASES, and GeneCards databases. Shared genes were identified across cancers, and functional enrichment analysis revealed their involvement in key cancer-related pathways, particularly the cell cycle. Protein–protein interaction networks identified ten candidate hub biomarkers (HGF, CDK1, CCNB1, RRM2, KIF14, DCN, SERPINE1, CCNA2, DLGAP5, and MAD2L1) consistently dysregulated across all four cancers. Survival analysis supported their potential as therapeutic targets, correlating with poor prognosis. These findings highlight candidate pan-cancer biomarkers for improved diagnosis and therapy. Full article

Background: Resistant hypertension poses a significant therapeutic challenge, often leading to severe polypharmacy. Renal denervation (RDN) has re-emerged as a valuable adjunctive intervention for blood pressure control. Case Presentation: We report the case of a 64-year-old man (body mass index [BMI] 34 kg/m²) with long-standing resistant hypertension (RH), after previous percutaneous coronary intervention (PCI) to the left anterior descending artery, heart failure with preserved ejection fraction (HFpEF), and prior nephron-sparing surgery for clear cell renal carcinoma. Despite treatment with an extensive antihypertensive regimen encompassing nine pharmacological classes including diuretic therapy (angiotensin-converting enzyme inhibitor; calcium channel blocker, thiazide diuretic, β-blocker, α1-blocker, central α2-agonist, mineralocorticoid receptor antagonist, loop diuretic, long-acting nitrates), blood pressure remained severely uncontrolled on both home and office measurements. Persistent hypertension was accompanied by exertional dyspnoea and episodes of exertional chest discomfort. Following comprehensive evaluation and exclusion of secondary causes of hypertension, the patient underwent catheter-based renal denervation using the SymplicitySpyral™ (Medtronic) multi-electrode radiofrequency system. The procedure was associated with substantial and sustained improvement in blood pressure control, with mean 24 h ambulatory blood pressure measurements decreasing to 130/80 mmHg at six-month follow-up. Importantly, successful blood pressure reduction enabled major simplification of pharmacotherapy, including complete discontinuation of clonidine, loop diuretic therapy, and long-acting nitrates, together with marked dose reduction in doxazosin. Conclusions: This case illustrates the potential clinical utility of renal denervation in carefully selected patients with true resistant hypertension and pronounced sympathetic overactivity. Beyond achieving satisfactory blood pressure control, RDN may facilitate meaningful reduction in medication burden, potentially improving treatment adherence, quality of life, and long-term cardiovascular risk. Written informed consent was obtained from the patient for both the procedure and the publication of this case report. Full article

Renal cell carcinoma (RCC) is the most common malignancy of the urinary system, characterized by high incidence, mortality, and resistance to therapy. Its molecular heterogeneity presents challenges for effective precision treatment. RCC is highly heterogeneous, yet treatment guidelines rely predominantly on kidney renal clear cell carcinoma (KIRC) studies, neglecting other molecular subtypes, which limits therapy personalization for non-KIRC patients. This study aimed to explore the role of small ubiquitin-like modifier (SUMOylation)-associated genes in the progression and prognosis of RCC and its subtypes. We identified 298 SUMOylation-associated differentially expressed genes (DEGs), including 151 RCC-specific genes after excluding expression changes attributable to RCC subtype-specific variation. Ten core genes (PRKCG, PRKCQ, PRKCD, IRS4, SLC2A4, SLC27A1, SLC27A4, LCN2, S100A7, and S100A9) were identified, with LCN2 expression not only discriminates tumor from normal tissue but also separates KIRC from KICH/KIRP, proposing LCN2 as a potential second-step biomarker for KIRC identification on top of traditional histology. Inter-subtype RCC heterogeneity represented a key factor limiting predictive performance of the six prognostic signature genes (CREB3L1, GNA11, PFKM, PPARGC1A, PPP2R2C and PRKCG). Its 5-year AUC exceeded 0.7 for every individual RCC subtype in the TCGA training cohort, with pooled 5-year AUCs of 0.61 (TCGA training cohort) and 0.67 (independent PCAWG validation cohort). The prognostic risk model demonstrated strong predictive performance, with a C-index of 0.791 before calibration and 0.774 after calibration. Importantly, the C-index remained above 0.75 throughout the 60-month follow-up period, indicating stable and robust long-term prognostic accuracy. High-risk patients exhibited greater immune cell infiltration, indicating potential for immunotherapy. Following secondary screening, three RCC cell lines (BFTC909, CAKI1, and CAL54) and five target genes (PRKCD, SLC27A1, SLC27A4, LCN2 and GNA11) were identified as optimal candidates for subsequent mechanistic investigations. This study uncovers the prognostic and functional relevance of SUMOylation in RCC and offers a novel framework for biomarker development, therapeutic targeting, and immunotherapeutic stratification. Full article

Background/Objectives: Thymidylate synthase (TYMS) represents an important therapeutic target. Methods: In this study, TYMS expression was analyzed by immunohistochemistry on a tissue microarray containing 17,371 samples from 136 different tumor types. Results: TYMS staining was seen in 42.9% of 15,361 analyzable tumors, with weak staining in 35.4%, moderate in 5.7%, and strong in 1.8%. TYMS occurred in at least one case of 127 categories, of which 71 showed TYMS staining in at least 50% of cases, and 56 included at least one case with strong positivity. TYMS positivity occurred most commonly in lymphomas (81.3–96.5%), sarcomas and sarcomatoid carcinomas (33.3–100%), malignant melanoma (70.5–90.7%), cervical adenocarcinoma (78.3%), and squamous cell carcinomas of various sites (57.1–77.9%). High TYMS expression was linked to advanced pT (p = 0.0097), high grade (p < 0.0001), ER negativity (p < 0.0001), and PR negativity (p = 0.0002) in invasive breast cancer of no special type; high grade (p < 0.0050), high UICC stage (p = 0.0060), and nodal metastasis (p = 0.0120) in clear cell renal cell carcinoma (RCC); high grade (p < 0.05) and nodal metastasis (p = 0.0045) in papillary RCC; high Gleason grade (p < 0.0001) and advanced pT stage (p = 0.0149) in prostatic adenocarcinoma; high pT (p < 0.0001), nodal metastasis (p = 0.005), lymphatic (p = 0.0064) and venous invasion (p = 0.0005), left side location (p < 0.0001), and microsatellite instability (p < 0.0001) in colorectal adenocarcinoma; and high grade (p < 0.0001) in squamous cell carcinomas of different sites. Conclusions: TYMS is often overexpressed across different cancer entities and shows associations with several adverse histopathological parameters commonly used to describe tumor phenotypes. Full article

Background/Objectives: Prostate cancer is the second most frequent cancer among men and the 5th leading cause of cancer death among men worldwide. Identification of urine-derived biomarkers, such as exosomal miRNAs, in liquid biopsies for prostate cancer could be very beneficial for screening and active surveillance. Methods: Urine was collected from 42 patients with biopsy-proven evidence of prostate cancer and exosomes were extracted. Transcriptomic analysis was performed on the urine-derived exosomal miRNA and compared to the urine-derived exosomal miRNA profiles from 10 normal control donors and 15 von Hippel-Lindau (VHL) syndrome patients with clear cell renal cell carcinoma (ccRCC). Results: Urine-derived exosomal miRNA profiles of prostate patients were significantly different from normal control individuals. Significantly increased expression of miR-122-5p and decreased expression of miR-125-5p and miR-16-5p were observed in the urine-derived exosomes from prostate cancer patients. Significant upregulation of miR-30a-5p and downregulation of miR-320-5p, miR-320b, and miR-320c were observed in the urine-derived exosomes from both prostate cancer patients and VHL patients with ccRCC, indicating these miRNAs could be non-specific markers of urological cancer. Increased expression of miR-10a-5p and miR-30e-5p or miR-532-5p and miR-206 correlated with the presence of either extracapsular or perineural invasion, respectively. Conclusions: This study highlights the potential for urine-derived exosomal miRNA profiles to identify the presence of prostate cancer and predict clinical features, additionally showing that miRNA signals could be non-specific markers of urologic cancer types. Further validation studies are necessary to demonstrate the utility of urine-derived exosomal miRNA profiles as biomarkers for diagnosis or prognosis in prostate cancer. Full article

Background/Objectives: Clear cell renal cell carcinoma (ccRCC), the predominant malignant subtype of kidney cancer, is the leading cause of death among renal cell carcinoma patients. Although a subset of ccRCC patients benefit from select immune checkpoint inhibitors (ICIs), prognosis remains poor. While PD-1 and PD-L1 have been extensively studied, the prevalence and distribution of other immune checkpoints (ICs) and their relationship with epithelial-to-mesenchymal transition (EMT) remain poorly characterised. Here, we investigated the interplay between twenty ICs and EMT markers and assessed their combined prognostic relevance in ccRCC patients. Methods: Transcriptomic profiling and integrated bioinformatic analyses were performed, including differential expression, correlation analyses, survival analyses, forest plot analyses, ROC curve evaluation, and OncoPrint visualisation, complemented by analysis of single-cell RNA sequencing data, immunohistochemistry, and multiplex secretory IC (LegendPlex) assays. Results: Transcriptomic profiling of over 500 ccRCC tumours versus normal kidney tissue revealed dysregulation of ICs, particularly LAG3 and NT5E. Notably, expression of ICs, including LAG3 and NT5E, was associated with poor overall survival in 415 ccRCC patients. ICs that synergised with the EMT phenotype provided improved prognostic discrimination compared to individual ICs. Correlation analyses, single-cell RNA sequencing, and immunohistochemistry demonstrated an association between EMT-associated tumours and expression of LAG3 and NT5E. ROC analysis indicated modest prognostic performance of LAG3 and NT5E. Conclusions: Collectively, this study identifies an EMT–IC axis in ccRCC and demonstrates its relevance to tumour biology and patient outcomes, highlighting LAG3 and NT5E as potential prognostic markers and therapeutic targets that warrant further investigation. Full article

Background: Hypertension is a common comorbidity and risk factor for clear cell renal cell carcinoma (ccRCC), yet the molecular mechanisms linking these two diseases remain unclear. This study aimed to investigate hypertension-related molecular signatures in ccRCC using integrated multi-transcriptomic analyses. Method: Hypertension-related differentially expressed genes (DEHRGs) in ccRCC were identified by integrating transcriptomic data from the TCGA-KIRC cohort with the GeneCards database. Functional enrichment, WGCNA, machine learning, GSVA, survival analysis, and Mendelian randomization were performed to identify and characterize hub genes. Spatial and single-cell transcriptomic analyses were used to investigate tumor heterogeneity and predict candidate therapeutic compounds, which were subsequently evaluated in vitro. Results: Four hypertension-related hub genes—SCNN1G, CASR, KCNJ1, and WNK4—were identified and were mainly involved in ion transport, electrolyte homeostasis, and blood pressure regulation. Diagnostic models based on these genes showed good discriminatory performance between tumor and normal tissues, and the nomogram showed good calibration and potential clinical benefit. Higher hypertension-related transcriptional activity was associated with significantly poorer overall survival, while MR analysis suggested a genetic association with ccRCC risk. Spatial transcriptomics revealed pronounced spatial heterogeneity of SCNN1G, CASR, KCNJ1, and WNK4, with these hub genes predominantly enriched in stromal and immune regions. Single-cell-based drug screening identified candidate compounds predicted to have antitumor activity, among which epicatechin gallate (ECG) and pseudoginsenoside-F11 showed favorable tumor selectivity. Conclusions: This study systematically characterized hypertension-related molecular signatures in ccRCC and identified SCNN1G, CASR, KCNJ1, and WNK4 as key hub genes. These genes may contribute to the molecular association between hypertension and ccRCC. They also represent promising candidate biomarkers and therapeutic targets. Integrated spatial and single-cell analyses further identified pseudoginsenoside-F11 and ECG as potential therapeutic compounds and supporting a potential molecular association between hypertension and ccRCC. Full article

Background and Objectives: Clear cell renal cell carcinoma (ccRCC) demonstrates substantial molecular and clinical heterogeneity, limiting the prognostic accuracy of conventional staging system and complicating treatment selection. CT-based radiomics and radiogenomics have emerged as promising non-invasive approaches for predicting molecular biomarkers. This review aimed to evaluate the current evidence regarding CT-based radiogenomics for the prediction of molecular markers in ccRCC, with emphasis on methodological approaches, predictive performance, and clinical applicability. Materials and Methods: A comprehensive literature search of PubMed/MEDLINE, Scopus, and Cochrane Library databases was performed for original studies published between January 2012 and December 2025. Eligible studies included patients with histopathologically confirmed ccRCC, performed CT-based radiomics feature extraction, and investigated molecular or genetic biomarkers using machine learning (ML) methods. Data regarding CT acquisition phase, segmentation strategy, radiomics features, ML algorithms, investigated biomarkers, and model performance metrics were extracted. Results and Discussion: Twenty-five retrospective studies were included. CT-based radiomics demonstrated promising performance in predicting gene mutations, including Von Hippel–Lindau (VHL), Polybromo 1 (PBRM1), BRCA1-associated protein 1 (BAP1), SET domain containing 2 (SETD2), and Lysine demethylase 5C (KDM5C), with reported area under the curve (AUC) values reaching 0.987. Radiogenomic models also showed utility in assessing hypoxia-related pathways, lipid metabolism signatures, programmed cell death profiles, immune-related markers, and tumor microenvironment characteristics, including programmed death-ligand 1 (PD-L1), Cluster of Differentiation 68 (CD68+) tumor-associated macrophages (TAMs), Cytotoxic T-Lymphocyte–Associated Protein 4 (CTLA-4), Forkhead Box P3 (FOXP3), and Ki-67 proliferation index. Predictive performance varied across biomarkers, with AUCs generally ranging from 0.68 to 0.91. Random Forest (RF), Logistic Regression (LR), Support Vector Machine (SVM), Adaptive Boosting (AdaBoost), and Gradient Boosting algorithms were most commonly applied. Conclusions: CT-based radiogenomics represents a promising non-invasive tool for molecular characterization and risk stratification in ccRCC. Standardized multicenter prospective studies, methodological homogeneity, and external validation are required before routine clinical implementation. Full article

Introduction: Small hyperechoic renal masses are frequently detected incidentally on conventional ultrasound and are often presumed to represent benign lesions, particularly angiomyolipomas. However, malignant renal tumors, including renal cell carcinoma, may also appear hyperechoic when small, creating a diagnostic challenge at first-line imaging. This study aimed to evaluate the feasibility and exploratory diagnostic performance of B-mode ultrasound radiomics for differentiating benign and malignant small hyperechoic renal masses. Methods: This retrospective single-center study included adult patients with incidentally detected small hyperechoic renal masses measuring ≤3 cm and examined between July 2022 and April 2025. All lesions underwent standardized B-mode ultrasound assessment and multidisciplinary review. Final diagnosis was established by histopathology when available or by longitudinal ultrasound follow-up stability for lesions considered benign. Lesions were manually segmented on representative B-mode DICOM images, and original radiomic features were extracted using PyRadiomics version 3.0 according to standardized definitions compatible with the Image Biomarker Standardisation Initiative framework. A total of 114 original radiomic features were extracted from each lesion. The primary comparison was benign versus malignant lesions. Diagnostic performance was assessed using feature-level receiver operating characteristic analysis. Results: Forty-two lesions were included in the final radiomic cohort, including 26 malignant renal cell carcinomas and 16 benign angiomyolipomas. Malignant lesions included papillary renal cell carcinoma, chromophobe renal cell carcinoma, and clear-cell renal cell carcinoma. All malignant lesions were histologically confirmed. Among benign lesions, 14 angiomyolipomas were classified based on longitudinal ultrasound stability, whereas 2 were confirmed by ultrasound-guided percutaneous biopsy after mild dimensional increase during imaging surveillance. Among the extracted radiomic features, firstorder_Variance and firstorder_MeanAbsoluteDeviation showed the highest exploratory discriminatory performance, each achieving an area under the receiver operating characteristic curve of 0.837. Both features are first-order measures of gray-level dispersion within the segmented lesion. Higher values were observed in malignant lesions, suggesting greater intralesional grayscale heterogeneity compared with benign angiomyolipomas. Conclusions: B-mode ultrasound radiomics is feasible for the quantitative assessment of small hyperechoic renal masses and may provide complementary information for differentiating benign angiomyolipomas from malignant renal cell carcinomas. firstorder_Variance emerged as a representative candidate imaging biomarker of grayscale dispersion, with firstorder_MeanAbsoluteDeviation showing concordant performance as a related dispersion measure. These findings should be considered preliminary and hypothesis-generating and require validation in larger multicenter cohorts before clinical implementation. Full article

Background/Objectives: The heterogenous nature of renal cell carcinomas (RCCs) is increasingly recognized. The purpose of this proof-of-concept pilot study was to evaluate correlations between multiparametric MRI (mpMRI)-derived and histopathological parameters in RCCs from spatially matched regions on both MRI and pathological examination to support targeted biopsy planning. Methods: In this prospective single-center pilot study, patients with solid renal tumors ≥2 cm undergoing nephrectomy were prospectively enrolled. Each patient underwent preoperative 3.0T-mpMRI including T2-weighted and pre-/post-contrast T1-weighted sequences, chemical-shift imaging, IVIM-DWI, and T1/T2*/R2 mapping. Tumor regions were defined jointly by a pathologist and radiologist, and identical regions of interest were assessed for each tumor region across all sequences to gain quantitative mpMRI-derived parameters. Histopathology provided quantitative regional fractions of viable tumor, fibrosis, hemorrhage, and cystic/necrotic components. Spearman’s rank correlations and univariable linear regression assessed associations between mpMRI and histopathological parameters on a regional level. Results: Across 49 tumor regions in eight patients (65.3% clear cell, 34.7% papillary RCCs), the mean viable tumor fraction was 80.9% (SD 17.6). The viable tumor fraction showed inverse correlations with nephrographic and delayed phase signal intensity changes (rho = −0.59/rho = −0.51), T1 values (rho = −0.56), true diffusion coefficient D (rho = −0.47), and ADC (rho = −0.45), and a positive correlation with R² times (rho = 0.55). Delayed and nephrographic phase signal intensity changes (R² = 0.41/R² = 0.39) were the strongest single exploratory imaging correlates of viable tumor fraction. Conclusions: These findings support the feasibility of quantitative mpMRI parameters to capture regional intratumoral heterogeneity in RCCs, thereby highlighting regions with high viable tumor burden, which may help to refine the imaging-based assessment of RCCs in the future. Full article

Unc-51-like kinase 3 (ULK3) is a key member of the ULK serine/threonine kinase family. Aberrant ULK3 expression has been increasingly linked to tumorigenesis and malignant progression in multiple cancer types. However, the precise role of ULK3 in tumor initiation and progression remains incompletely understood. Leveraging integrated multi-omics data from The Cancer Genome Atlas (TCGA), the Genotype-Tissue Expression (GTEx) project, and the Clinical Proteomic Tumor Analysis Consortium (CPTAC), we systematically characterized the expression of ULK3 at both the transcript and protein levels across 33 cancer types. We also evaluated genomic alterations, prognostic significance, alternative splicing, pathway enrichment, tumor stemness, immune infiltration, and immunotherapy-related biomarkers. In parallel, we investigated the function of ULK3 in prostate cancer PC-3 cells using cellular localization analysis, wound-healing assays, and MTT assays. We further applied Connectivity Map (CMap) screening and molecular docking to identify candidate ULK3 activators. ULK3 was significantly upregulated in 13 cancer types, including Bladder Urothelial Carcinoma, Breast Invasive Carcinoma, and Lung Adenocarcinoma. In contrast, ULK3 was downregulated in Cholangiocarcinoma and Head and Neck Squamous Cell Carcinoma. High ULK3 expression was associated with poor overall survival in Adrenocortical Carcinoma, Kidney Renal Clear Cell Carcinoma, and Skin Cutaneous Melanoma. Copy number amplification contributed to ULK3 overexpression. A recurrent A206V missense mutation was detected in the protein kinase (Pkinase) domain. Genes co-expressed with ULK3 were enriched in RNA splicing, methylation, oxidative phosphorylation, and energy metabolism. ULK3 expression showed positive correlations with tumor stemness indices and m1A/m5C/m6A RNA modification regulators. From an immunological perspective, high ULK3 expression was associated with lower Immune Score, increased M2 macrophage infiltration, and co-expression of PD-L1, CTLA4, and LAG3 in most cancers. ULK3 expression was also correlated with Tumor Mutational Burden in Kidney Renal Clear Cell Carcinoma and Rectum Adenocarcinoma. In addition, ULK3 expression was associated with Microsatellite Instability in Brain Lower Grade Glioma, Lung Adenocarcinoma, and Uterine Corpus Endometrial Carcinoma. ULK3 overexpression promoted proliferation and migration in PC-3 cells. Cephaeline was screened as a putative ULK3 activator. Overall, ULK3 expression and amplification were associated with poor clinical outcomes, tumor stemness, immunosuppression, and RNA dysregulation. These findings highlight the potential value of ULK3 as a pan-cancer diagnostic and prognostic biomarker and as a predictor of immunotherapy response, particularly in prostate cancer. Full article

Solid tumors frequently experience hypoxia during tumor progression, resulting in profound metabolic alterations. This phenomenon is particularly pronounced in clear-cell renal cell carcinoma (ccRCC) because of loss of the von Hippel–Lindau (VHL) tumor suppressor gene and constitutive activation of hypoxia-inducible factor (HIF) signaling. ccRCC is the most common subtype of kidney cancer, and durable therapeutic responses remain limited despite advances in immune checkpoint inhibition. Owing to its strong pseudohypoxic phenotype and extensive metabolic rewiring, ccRCC is widely regarded as a metabolic disease. These alterations generate a unique immune landscape characterized by abundant immune-cell infiltration together with profound T-cell dysfunction and exhaustion. This paradoxical “immune-hot yet immunosuppressed” phenotype is largely driven by hypoxia-associated immunometabolic reprogramming within tumor cells and the tumor microenvironment (TME). Several metabolic pathways are critically involved in this process, including lactate acidosis, arginine (Arg) depletion, tryptophan (Trp) depletion, kynurenine (Kyn)-mediated T-cell exhaustion, and adenosine-driven immune suppression. This review summarizes the current understanding of hypoxia-driven immunometabolic interactions in ccRCC and discusses how targeting these pathways may improve future therapeutic strategies against this aggressive malignancy. Full article

Background: Renal cell carcinoma accounts for nearly 15,000 deaths annually in the US, and approximately 30–40% of patients present with metastatic disease (mRCC). The advent of immune checkpoint inhibitors (IO) and tyrosine kinase inhibitors (TKI) has revolutionized the treatment paradigm of patients with mRCC. However, the role of cytoreductive nephrectomy (CN) in the IO-TKI era, particularly for rare and understudied histologies such as non-clear-cell RCC, remains poorly understood. Methods: We conducted a retrospective cohort study of patients with metastatic non-clear-cell RCC. Patients were stratified by receipt of CN. Baseline demographic, clinical, histologic, and metastatic site variables were collected. Overall survival was analyzed using Kaplan–Meier methods and compared with the log-rank test. Cox proportional hazards regression was performed to identify independent predictors of survival, including CN, systemic therapy, year of diagnosis, histology, and metastatic sites. Results: Among 2753 patients with metastatic nccRCC, 1654 (60.1%) underwent CN and 1099 (39.9%) did not undergo CN. The 2-year and 5-year OS rates were 35.52% and 19.22% in the CN group versus 18.53% and 7.47% in the non-CN group (p < 0.001). In the doubly robust IPTW-weighted multivariable Cox regression analysis, CN was associated with improved overall survival, corresponding to a 40% lower risk of death compared with no CN (HR 0.60, 95% CI 0.54–0.66; p < 0.001). Additionally, more recent treatment eras were associated with progressively improved overall survival, with patients diagnosed between 2015 and 2017 and 2018 onward demonstrating significantly improved OS compared with those diagnosed between 2004 and 2014. Conclusions: Our study demonstrates that CN was associated with improved OS in patients with non-clear-cell mRCC by reducing the risk of death by 40% after adjusting for baseline characteristics. These findings emphasize the role of CN even in the IO-TKI era for the management of patients with non-clear-cell mRCC. However, these findings should be interpreted in the context of the retrospective study design, potential selection bias, and lack of granular systemic therapy data within the NCDB. Full article

Clear cell renal cell carcinoma (ccRCC) accounts for approximately 75% of renal cell carcinomas and is defined by near-universal VHL inactivation, leading to constitutive HIF stabilisation, metabolic reprogramming, and an immunologically distinct tumour microenvironment (TME). Although ccRCC is characterised by abundant immune infiltration, this paradoxically correlates with poor prognosis, reflecting a TME that imposes interconnected physical, immunological, and metabolic barriers to effective immunotherapy. Chimeric antigen receptor (CAR)-based therapies have revolutionised the treatment of haematological malignancies, but their translation to ccRCC has encountered substantial hurdles. The first-in-human trial targeting carbonic anhydrase IX (CAIX) was limited by on-target off-tumour toxicity and CAR immunogenicity—lessons that fundamentally reshaped the field. CD70 has since emerged as the dominant clinical target, expressed in over 80% of ccRCCs with a highly restricted normal tissue distribution. The phase I COBALT-RCC trial of CTX130, an allogeneic CRISPR-Cas9-edited CD70-directed CAR-T cell product, provided formal proof of concept, achieving disease control in 81.3% of heavily pretreated patients and a durable complete response now exceeding three years—the first such sustained remission reported for any CAR-T cell product in a solid malignancy. Nevertheless, the low frequency of durable responses and universal loss of CAR-T cell persistence by day 28 underscore that major barriers remain. Beyond CD70, the field has diversified across multiple platforms, including CAR–natural killer (NK) cells, CAR–natural killer T (NKT) cells, and CAR–macrophages, each offering distinct biological advantages. This review synthesises current knowledge of the ccRCC TME, the preclinical landscape of CAR-based therapies, and emerging clinical evidence from more than 30 registered trials. We discuss target antigens; engineering strategies to overcome TME barriers, including cytokine armouring, chemokine receptor co-expression, switch receptors, and metabolic reprogramming; and rational combination approaches. We argue that the convergence of optimised target selection, cellular engineering, combination strategies, and biomarker-driven trial design may ultimately improve outcomes for patients with ccRCC. However, achieving a cure remains an aspirational goal, and significant barriers must first be overcome. Full article

Background/Objectives: The double-strand break repair protein MRE11 forms the core of the MRE11/RAD50/NBS1 (MRN) complex. Cancers with reduced MRE11 expression have been suggested to be more sensitive to radio-chemotherapy and may be subject to synthetic lethality. The aim of this study was to assess the prevalence of MRE11 deficiency and the potential role and clinical significance of elevated and/or reduced MRE11 expression in human cancer. Methods: A tissue microarray containing 14,966 samples from 134 different tumor entities was analyzed for MRE11 by immunohistochemistry. Results: In normal tissues, strong nuclear MRE11 staining occurred in almost all cell types. In cancers, nuclear MRE11 staining was strong in 11,797 (91.0%), moderate in 1018 (7.9%), weak in 86 (0.7%), and completely absent (MRE11 deficiency) in 55 (0.4%) of 12,956 informative tumor samples. Only six tumor entities had more than one MRE11-deficient cases including hepatocellular carcinoma (9 of 193), intestinal type gastric adenocarcinoma (4 of 208), endometrioid endometrial carcinoma (5 of 268), pulmonary adenocarcinoma (2 of 165), colorectal adenocarcinoma (CRC, 16 of 2183), and clear cell renal cell carcinoma (ccRCC, 7 of 1011). Reduced MRE11 staining was associated with mismatch repair deficiency (dMMR) in CRC and in gastric adenocarcinoma (p < 0.0001 each), advanced pT stage (p = 0.0003) and L1 status (p = 0.0019) in testicular seminoma, high grade (p < 0.05), advanced pT (p < 0.0001), and high UICC stage (p = 0.0014) in ccRCC, advanced pT stage in high-grade serous ovarian carcinoma (p = 0.0396), and nodal metastases in papillary thyroid cancer (p = 0.0332). Conclusions: MRE11 is highly expressed in most cancers. Reduced MRE11 expression is associated with aggressive phenotype in multiple cancer types. The potential to exploit MRE11 deficiency as a target for synthetic lethality deserves to be further explored. Full article