CcRCC has the characteristics of high aggression, high metastasis, high mortality, wide tumour heterogeneity and variable clinical course. The purpose of this study was to explore the potential value of lncRNAs-related to DNA damage repair (DDR) in predicting the prognosis of ccRCC by construction and verification a novel prognostic model.

RNA-seq data and clinical data of ccRCC were downloaded from public databases. Subsequently, Pearson correlation analysis and differential expression analysis were performed to identify DElncRNAs-related to DDR. Then, through univariate Cox analysis and LASSO analysis, the DElncRNAs-related to DDR associated with prognosis were screened for the construction of novel risk score prognostic model. In addition, functional annotation, tumour mutation burden, immune correlation and drug sensitivity analyses were performed based on risk score to assess the characteristics of patients in different risk score groups.

Based on univariate Cox analysis and LASSO analysis, four best DElncRNAs-related to DDR were selected. Subsequently, a novel risk score prognostic model based on these four DElncRNAs was constructed through LASSO. Multivariate Cox analysis showed that risk score and age were independent prognostic factors for ccRCC (p < 0.05). Functional enrichment analysis showed that DDR-related biological processes were mainly enriched in the high risk group. The highly mutated genes in the high and low risk groups were the same (VHL, PBRM1 and TTN), but they also had their own unique mutated genes. Pearson correlation analysis showed that the risk score was significantly (p < 0.05) positively correlated with the infiltration degree of CD8 T cells evaluated by six algorithms. In addition, it was found that the high and low risk groups had different sensitivities to the drugs Etoposide, Imatinib, Sorafenib, Bosutinib and Sunitinib.

A novel prognostic model was constructed based on four DElncRNAs-related to DDR. The model has satisfactory accuracy in predicting survival of ccRCC patients.

Renal cell carcinoma (RCC) is a heterogeneous malignancy with diverse gene expression patterns, molecular landscapes, and differentiation characteristics of tumor cells. It is imperative to develop molecular RCC classification based on tumor cell differentiation for precise risk stratification and personalized therapy.

We obtained scRNA-seq profiles from GSE159115 and bulk RNA-seq profiles from TCGA-KIRC cohort. We then performed scRNA-seq cluster analysis, monocle2 pseudotime analysis, and prognostic analysis to obtain tumor cell differentiation-related prognostic genes (TCDGs). Subsequently, we conducted consensus clustering to construct the RCC tumor cell differentiation-related prognostic classification (RCC-TCDC) and implemented prognostic and multi-omics analyses. Moreover, we utilized Lasso regression to help develop a multivariable prognostic model. In addition, we performed correlation analysis and Cmap algorithm for regulatory network establishment and candidate inhibitor prediction. We eventually included 370 kidney neoplasm patients in Xinhua cohort to undergo immunohistochemical staining and scoring for classification and comprehensive statistical analyses, including Chi-square tests, Kaplan-Meier survival analyses, and multivariable Cox regression analysis .

32 TCDGs were identifiedand RCC-TCDC was constructed to classify TCGA-KIRC patients into RCC-low differentiation (RCC-LD) (S100A11+ SH3BGRL3+, high risk), RCC-moderate differentiation (TSPAN7+, medium risk), and RCC-high differentiation (RCC-HD) (AQP1+ NPR3+, low risk). Notably, RCC-LD was validated as anindependent risk factor for both OS (p = 0.015, HR = 14.0, 95%CI = 1.67-117.8) and PFS (p = 0.010, HR = 4.0, 95%CI = 1.39-11.7) of RCC patients in Xinhua cohort, taking RCC-HD as reference.

We constructed and validated a robust molecular classification system, RCC-TCDC, elucidating three distinct RCC subtypes.

RNA N6-methyladenosine (m6A) plays diverse roles in RNA metabolism and its deregulation contributes to tumor initiation and progression. Clear cell renal cell carcinoma (ccRCC) is characterized by near ubiquitous loss of VHL followed by mutations in epigenetic regulators PBRM1, SETD2, and BAP1. Mutations in SETD2, a histone H3 lysine 36 trimethylase (H3K36me3), are associated with reduced survival, greater metastatic propensity, and metabolic reprogramming. While m6A and H3K36me3 deregulation are separately implicated in renal tumorigenesis, H3K36me3 may participate directly in m6A targeting, but the m6A-H3K36me3 interplay has not been investigated in the context of ccRCC. Using RCC-relevant SETD2 isogenic knockout and rescue cell line models, we demonstrate a dynamic redistribution of m6A in the SETD2 depleted transcriptome, with a subset of transcripts involved in metabolic reprogramming demonstrating SETD2 dependent m6A and expression level changes. Using a panel of six histone modifications we show that m6A redistributes to regions enriched in gained active enhancers upon SETD2 inactivation. Finally, we demonstrate a reversal of transcriptomic programs involved in SETD2 loss mediated metabolic reprogramming, and reduced cell viability through pharmacologic inhibition or genetic ablation of m6A writer METTL3 specific to SETD2 deficient cells. Thus, targeting m6A may represent a novel therapeutic vulnerability in SETD2 mutant ccRCC.

Clear cell renal cell carcinoma (ccRCC) is aggressive and heterogeneous, resulting in poor prognosis due to frequent metastasis. Napsin A, an aspartic proteinase encoded by the NAPSA gene, is involved in protein processing and is expressed in the kidney and lung, but its function is not well understood. Studying ccRCC's molecular characteristics, including Napsin A, is vital for enhancing diagnostics and treatment.

Single-cell RNA sequencing data from the GEO database (GSE210042) were analyzed, including seven tumor and two normal samples. The Seurat package was used for data preprocessing, clustering, and visualization. Differential expression and enrichment analyses were conducted between tumor and normal cells, and cell-to-cell communication was assessed between NAPSA + and NAPSA- cells. The correlation between NAPSA expression and EMT score was analyzed using TCGA-KIRC data. In vitro experiments involved transfecting OS-RC-2 and Caki-1 ccRCC cell lines with siRNA targeting NAPSA. Effect on the cellular EMT process induced by TGF-β1 was assessed by immunofluorescence staining.

NAPSA was primarily expressed in podocytes and ccRCC epithelial cells, with significantly reduced levels in tumor tissues associated with poor prognosis. NAPSA downregulation may influence various biological pathways and enhance communication with tumor-associated macrophages and mast cells. Silencing NAPSA increased TGF-β1-induced epithelial-mesenchymal transition (EMT).

The study highlights NAPSA's expression characteristics and potential role in ccRCC, suggesting it may serve as a biomarker. Further research is needed to elucidate NAPSA's mechanisms and explore its applications in precision medicine.

Renal cell carcinoma (RCC) remains a therapeutic challenge despite recent immunotherapy advances. We identified ENPP3 and SIRPα as significantly overexpressed in RCC tissues with positive correlation and prognostic relevance. Based on these findings, we developed a novel bispecific antibody simultaneously targeting tumor-associated ENPP3 and macrophage checkpoint SIRPα. The ENPP3-SIRPα bispecific antibody demonstrated specific binding to both targets and effectively blocked CD47-SIRPα interaction in vitro. In vivo this bispecific approach exhibited superior anti-tumor efficacy compared to monotherapies or their combination as separate agents. Mechanistic studies confirmed that the therapeutic effect was macrophage-dependent, with enhanced phagocytosis of tumor cells. Importantly, the bispecific antibody maintained a favorable safety profile with no significant hematological abnormalities observed during treatment. These findings demonstrate that simultaneous targeting of ENPP3 and SIRPα represents a promising immunotherapeutic strategy for RCC, combining tumor-specific targeting with immune checkpoint inhibition while mitigating potential toxicities associated with systemic SIRPα blockade.

Succinylation is a relatively common post-translational modification. It occurs in the cytoplasm, mitochondria, and the nucleus, where its essential precursor, succinyl-CoA, is present, allowing for the modification of non-histone and histone proteins. In normal cells, succinylation levels are carefully regulated to sustain a dynamic balance, necessitating the involvement of various regulatory mechanisms, including non-enzymatic reactions, succinyltransferases, and desuccinylases. Among these regulatory factors, sirtuin 5, the first identified desuccinylase, plays a significant role and has been extensively researched. The level of succinylation has a significant effect on multiple metabolic pathways, including the tricarboxylic acid cycle, redox balance, and fatty acid metabolism. Dysregulated succinylation can contribute to the progression or exacerbation of various urinary diseases. Succinylation predominantly affects disease progression by altering the expression of key genes and modulating the activity of enzymes involved in vital metabolic processes. Desuccinylases primarily affect enzymes associated with Warburg's effect, thereby affecting the energy supply of tumor cells, while succinyltransferases can regulate gene transcription to alter cell phenotype, thereby involving the development of urinary diseases. Considering these effects, targeting succinylation-related enzymes to regulate metabolic pathways or gene expression may offer a promising therapeutic strategy for treating urinary diseases.

Urologic malignancies, encompassing cancers of the kidney, bladder, and prostate, represent approximately 25 % of all cancer cases. Recent advances have enhanced our understanding of PVT1's crucial functions. Long noncoding RNAs influence both the onset and development of cancer, as well as epigenetic alterations. Recent findings have focused on PVT1's mechanism of action across several malignancies, particularly urologic cancers. Understanding the various functions of PVT1 linked to cancer is necessary for the development of cancer detection and treatment when PVT1 is dysregulated. Furthermore, recent advancements in genomic and epigenetic research have elucidated the complex regulatory networks that control PVT1 expression. Comprehending the intricate role of PVT1 Understanding the complex function of PVT1 in urologic cancers has substantial clinical implications. Here, we summarize some of the most recent findings about the carcinogenic effects of PVT1 signaling pathways and the possible treatment strategies for urological malignancies that target these pathways.

Clear cell renal cell carcinoma (ccRCC) is a prevalent and aggressive malignancy, with the von Hippel-Lindau (VHL) gene playing a critical role in its pathogenesis. However, the association between VHL gene variants and sporadic ccRCC risk remains unexplored in the Indian population. This study aimed to investigate the somatic and germline variants of the VHL gene in sporadic ccRCC patients from West Bengal, India, and their association with disease risk and clinicopathological parameters.

A total of 210 ccRCC patients and 255 ethnicity-matched healthy controls were enrolled. Genomic DNA from blood and tissue samples was analyzed using PCR-based Sanger sequencing. The association of VHL variants with ccRCC risk was assessed using Chi-square tests. The impact of genetic variants on patient clinicopathological features and overall survival was evaluated using Kaplan-Meier survival analysis and Cox proportional hazards models.

We identified twenty-three single nucleotide variants (SNVs) in the VHL gene, including 3 novel variants, OR250433 T > G, OR125589 C > T and OQ627404 G > C. The intronic variant rs61758376 G > C and 3'UTR variant rs1642742 A > G were significantly associated with an increased risk of ccRCC (OR = 1.676, P = 0.0074; OR = 1.735, P = 0.0171, respectively). The rs1642742 GG genotype was also significantly associated with larger tumor size (P < 0.05) and advanced tumor stage (pT4). Kaplan-Meier analysis indicated poorer overall survival for patients with the rs1642742 GG genotype (log-rank P = 0.029).

Our study is the first to document the association of VHL gene variants with sporadic ccRCC risk and clinical outcomes in the Indian population. The identified variants, particularly rs61758376 and rs1642742, could serve as potential biomarkers for ccRCC susceptibility and prognosis.

This study aims to develop chimeric antigen receptor (CAR)-T cells specifically targeting B7-H3-expressing renal cell carcinoma (RCC) and to evaluate the feasibility of B7-H3 CAR-T therapy for RCC.

We analyzed B7-H3 expression in RCC using bioinformatics approaches and confirmed it in tissues and cell lines through immunohistochemical staining and Western blot analysis. A lentiviral vector containing a B7-H3 specific CAR was constructed and transfected into human T cells, with CAR expression verified by flow cytometry. Cytotoxic efficacy was evaluated in co-culture experiments, measuring the production of interferon-gamma (IFN-γ), interleukin-2 (IL-2), granzyme B, and lactate dehydrogenase (LDH) release. Xenograft models in nude mice were used to evaluate tumor growth inhibition by B7-H3 CAR-T cells.

B7-H3 was significantly expressed in RCC and associated with poor prognosis. Elevated levels of B7-H3 expression were validated in both RCC tissues and cell lines. A B7-H3-specific CAR-T cell was developed, achieving a CAR transduction efficiency of 39.85%, as assessed by flow cytometry. In vitro co-culture assays demonstrated that the CAR-T cells exhibited substantial cytotoxic activity against RCC cell lines, with this activity positively correlating with the effector-to-target ratio. Furthermore, the secretion levels of IFN-γ, IL-2, granzyme B, and LDH were significantly increased compared to the control groups. In vivo experiments further confirmed that B7-H3 CAR-T cells significantly inhibited tumor growth.

The current study suggests that B7-H3 CAR-T cells exhibit significant efficacy in targeting and eliminating RCC cells, indicating a promising cellular immunotherapy approach for RCC treatment.

Clear cell renal cell carcinoma (ccRCC) is the most prevalent form of kidney cancer, distinguished by intricate interactions between metabolic reprogramming, immune microenvironment dynamics, and genetic mutations. In this detailed investigation, we analyzed the ccRCC cohort from The Cancer Genome Atlas (TCGA) alongside 81 metabolic signaling pathways from the KEGG database. By utilizing Gene Set Variation Analysis (GSVA), we performed hierarchical clustering of patients based on their metabolic pathway activity profiles, identifying three distinct clusters with notable differences in pathway activity and survival outcomes. Cluster 1 displayed high metabolic activity and more favorable survival outcomes, while Cluster 3 was characterized by low metabolic activity and poorer prognosis. Clinical comparisons revealed significant disparities in gender, histological stage, and survival status, with Cluster 3 exhibiting a higher proportion of patients at advanced stages and those who had passed away. Genetically, Cluster 1 showed the highest mutation burden, with prominent mutations in genes such as VHL and PBRM1. Biological process analysis indicated that pathways like organic carboxylic acid metabolism and ATP synthesis were upregulated in Cluster 1 but suppressed in Cluster 3. Machine learning models (GBM, CoxBoost, and LASSO regression) enabled the identification of four pivotal genes-BCAT1, IL4I1, ACADM, and ACADSB-which were subsequently used to construct a multifactorial Cox regression model. This model successfully stratified patients into high- and low-risk groups, correlating with marked differences in immune activities. The high-risk group showed elevated expression of chemokines, TNF, and HLA molecules. Drug sensitivity analysis suggested that AKT inhibitor III was more effective in the low-risk cohort, while Bortezomib might be more beneficial for high-risk patients. Additionally, a clinical prediction model integrating risk scores and clinical factors demonstrated strong predictive power for patient survival. Methylation profiling of the core genes via the UALCAN platform revealed distinct epigenetic signatures in ccRCC, providing deeper insight into the disease's molecular mechanisms. This study contributes to a more comprehensive understanding of ccRCC and proposes valuable directions for personalized treatment strategies and enhanced patient management.

Clear cell renal cell carcinoma (ccRCC) represents the most lethal form of kidney cancer, with a significant number of patients experiencing tumor progression. Succinylation modification is a novel post-translational modification (PTM) that refers to modifying a protein with a succinyl group, which most frequently happens to lysine residues. Recent studies have revealed that abnormal succinylation, altered protein activity, dysfunctional roles in energy metabolism, and subsequent epigenetic modifications are linked to the onset and progression of conditions like inflammation, cancer, and other diseases. No studies have offered a comprehensive analysis of succinylation modification in ccRCC or clarified the mechanisms by which this modification operates within disease progression. In this study, we applied quantitative proteomics and succinylation modification omics to extensively examine the global proteome and succinylation modification changes in ccRCC tissues. Using high-throughput liquid chromatography-mass spectrometry, we identified 4801 lysine succinylation modification sites across 1274 proteins in ccRCC and adjacent non-cancerous tissues. Additionally, 434 succinylation sites within 328 proteins displayed significant differential modification in ccRCC (fold change (FC) > 1.5 or p < 0.05). Notably, the succinylated proteins were primarily associated with energy metabolism pathways, including fatty acid elongation, glyoxylate and dicarboxylate metabolism, the tricarboxylic acid cycle, and oxidative phosphorylation, and were predominantly located within the mitochondria. This study is the first to present a global proteomic profile and a detailed succinylation modification landscape in ccRCC. These findings introduce new potential approaches for treating ccRCC by reversing abnormal succinylation modifications.

Clear cell renal cell carcinoma (ccRCC) is the predominant subtype of renal cancer, with a poor prognosis driven by therapy resistance and a propensity for recurrence. Tumor microenvironment (TME)-associated fibrosis accelerates disease progression by fostering immune evasion. Neuropilin-1 (NRP1), a key mediator in fibrotic signaling and cancer biology, has been implicated in these processes. However, the genetic correlation between fibrogenesis and ccRCC remains largely unexplored, necessitating a focused analysis of fibrogenesis-related genes (FRGs) to identify novel prognostic markers and therapeutic strategies.

This study utilized an integrative bioinformatics framework to identify prognosis-associated fibrogenesis-related genes (pFRGs) and applied non-negative matrix factorization (NMF) to stratify ccRCC patients based on fibrotic signatures. A machine learning-derived prognostic model was developed to categorize patients into high-risk and low-risk groups, with tumor microenvironment (TME) features analyzed across these subgroups. The pro-tumorigenic role of NRP1 via the TGF-β/SMAD signaling pathway was validated in vitro and in vivo.

Twelve pFRGs were identified, with elevated expression correlating with reduced survival. NMF revealed two ccRCC subtypes with different fibrotic and immune profiles. The high-fibrosis subtype showed worse survival and a pro-tumorigenic TME. The risk model demonstrated robust predictive performance (AUCs: 0.738, 0.731, 0.711 for 1-, 2-, and 3-year survival). High-risk patients, marked by immune dysfunction, exhibited worse survival but greater immunotherapy sensitivity. Among the pFRGs, NRP1 was upregulated in ccRCC, and paradoxically associated with favorable prognosis in TCGA, primarily due to stromal enrichment. In vitro and in vivo experiments confirmed that NRP1 promotes ccRCC proliferation, migration, and invasion by enhancing TGF-β/SMAD-driven epithelial-mesenchymal transition (EMT).

Fibrosis is a critical driver of ccRCC progression, linking fibrogenesis-related genes to poor prognosis, immune suppression, and tumor aggressiveness. NRP1 was identified as a central regulator of fibrosis-induced tumor progression through the TGF-β/SMAD signaling pathway. Combining NRP1 inhibition with anti-fibrotic therapies presents a potential strategy for enhancing therapeutic outcomes in ccRCC.

Significant advances in the management, in particular the treatment, of renal cell carcinoma (RCC) has have been made over the years. However, it is not clear whether these advances reduce the disease burden of RCC at the population level.

Using data from the Surveillance, Epidemiology, and End Results database, we estimated the temporal trends of RCC incidence, incidence-based mortality (IBM), and survival rates in the United States (US) from 1992 to 2019.

From 2008 to 2019, the incidence increased slowly at 1.1% annually (95% CI: 0.6% to 1.5%). The overall IBM rate of RCC increased by 6.8% per year (95% CI: - 1.1% to 15.3%) between 1994 and 1997, plateaued between 1997 and 2015, and then decreased nonsignificantly after 2015. During the study period, the overall Five year survival rate of RCC continuously increased from 53.69 in 1992 to 72.90% in 2014, with the best improvement observed for RCC patients with distant disease. However, we projected that, given the current trends, the incidence of RCC in the US will continue to increase from 6.92 per 100,000 in 2015-2019 to 9.59 per 100,000 in 2040-2044.

Over the years, the mortality of RCC has been decreased reducing at the US population level mainly because the considerably significantly improved survival of RCC patients at all stages through the advances in treatment. However, the overall incidence of RCC is continuously increasing, indicating that more effective preventive strategies should be developed to reduce the disease burden of RCC.

Solitary radius metastasis as the initial presentation of renal cell carcinoma is extremely rare. Here we present the bone scintigraphy findings of a 72-year-old man who complained of left wrist pain for 6 months. The 99mTc-MDP bone scintigraphy demonstrated intense ring-like MDP uptake in the distal left radius. Finally, solitary radius metastasis from renal cell carcinoma was confirmed.

To explore whether there is a relationship between perirenal fat area (PFA) and the pathological types of renal cell carcinoma (RCC).

Two hundred ninety-seven cases of RCC patients were included in our study, which is a retrospective analysis. Based on pathological type, we divided the 297 RCC patients into two groups: the clear cell renal cell carcinoma (ccRCC) group (236 cases) and the non-clear cell renal cell carcinoma (non-ccRCC) group (61 cases). Computed tomography (CT) images at the renal vein level were used to measure PFA. A multivariate logistic regression model was employed to examine the connection between various pathological types of RCC and PFA.

Significant differences were observed between ccRCC and non-ccRCC patients in PFA (P = 0.007), contralateral PFA (P = 0.011), weight (P = 0.002), BMI (P < 0.001), pathological stage 1 (P = 0.010), and pathological stage 2 (P = 0.002). To study the link between pathological subtypes and PFA, a multivariate logistic regression model was employed. Stratifying patients by tumor location in the kidney, the multivariate logistic regression analysis showed that when the tumor is located outside the polar lines of the kidney (OPLK), for every 1 cm2 increase in PFA, the probability of developing ccRCC increases by 5% [1.05 (1.01, 1.10) P = 0.0153]. Furthermore, after stratifying patients by tumor location and pathological stage, it was found that in T1 stage patients with tumors located OPLK, for every 1 cm2 increase in PFA, the probability of developing ccRCC increases by 6% [1.06 (1.01, 1.11) P = 0.0300].

When the tumor is located OPLK in T1 stage patients, PFA is positively correlated with ccRCC. Perirenal adipose tissue may be a risk factor for ccRCC.

Clear-cell renal cell carcinoma (ccRCC) is a highly aggressive malignancy that originates in the kidney. It often exhibits a limited response or can be refractory to a wide range of anti-cancer therapies, including tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors. Ferroptosis is a form of oxidative, iron-dependent cell death characterized by lipid peroxidation. Targeting ferroptosis may offer a promising alternative therapeutic strategy for cancer cells that are resistant to existing treatments. The impact of ferroptosis-related genes on the prognosis of ccRCC patients is still not fully understood. In this study, we identified 30 differentially expressed ferroptosis-related genes in ccRCC samples compared to normal tissues using data from The Cancer Genome Atlas (TCGA). Lasso regression analyses, along with Kaplan-Meier analysis, were conducted to identify genes associated with prognosis. Based on scRNA-seq and spatial transcriptome analysis, we identified specificity of MIOX in ccRCC. Furthermore, MIOX demonstrated the highest significance, highlighting its independent prognostic value as a single gene in ccRCC. Our findings suggest that MIOX could serve as potential targets for therapeutic interventions in ccRCC.

Postoperative non-metastatic clear cell renal cell carcinoma (nccRCC) patients face the risk of tumor recurrence and metastasis. However, prognosis assessment for nccRCC remains time-consuming and subjective. In the current diagnostic landscape, computed tomography (CT) images provide macro-scale anatomical information, and whole-slide images (WSIs) offer micro-scale details that are inaccessible to CT imaging. To address this gap, the study proposes a multimodal approach that leverages both CT and WSI data to develop an automated model for postoperative risk stratification in nccRCC.

This study proposes a multimodal model named the Radiology-Pathology Fusion Network (RPF-Net), which employs self-attention, graph-attention, and dynamic attention fusion mechanisms to integrate CT images and WSIs for classifying nccRCC patients into low-risk and intermediate-high-risk groups per the University of California, Los Angeles, Integrated Staging System (UISS) criteria. The proposed model is divided into three steps. First, the ResNet-50 and 3D ResNet-50 are used as feature extractors to respectively extract representative feature maps from WSIs and CT images. Second, a dual-branch module is designed to extract global and local features of the WSIs. Finally, a multilayer dynamic attention fusion (MDAF) module is developed to facilitate cross-modal feature interaction and predict the risk stratification results.

The area under the curve (AUC), accuracy, precision, and F1 Score of the RPF-Net on the internal validation set are 0.949±0.013, 0.894±0.019, 0.895±0.020, and 0.894±0.019, respectively. Furthermore, the RPF-Net shows robust generalization, achieving an AUC of 0.901 on the external validation set and 0.924 on the public dataset.

The RPF-Net models the diagnostic process of multimodal data and shows strong generalization and excellent performance. This model may be a potential tool to facilitate clinical risk stratification and management for postoperative nccRCC patients.

Clear cell renal cell carcinoma (ccRCC) is the most prevalent type of renal malignancy, and the deubiquitinase USP3 has been implicated as a critical factor in tumor biology. However, the precise mechanisms by which USP3 contributes to ccRCC progression remain unclear. This study investigates the role of USP3 in ccRCC and elucidates its underlying molecular mechanisms. Data from TCGA and GTEx databases showed elevated USP3 expression in ccRCC tissues and cell lines compared to normal renal tissues. Further analysis using qPCR and Western blot confirmed this upregulation in ccRCC cell lines. Functional assays revealed that silencing USP3 significantly impaired cell proliferation, migration, and invasion, while promoting apoptosis. Additionally, co-immunoprecipitation assays demonstrated an interaction between USP3 and MYC, with subsequent ubiquitination assays showing that USP3 regulates MYC stability. USP3 depletion also led to alterations in glycolysis-related gene expression, which could be partially reversed by MYC overexpression. These findings suggest that USP3 modulates ccRCC progression by stabilizing MYC, highlighting its potential as a therapeutic target in ccRCC treatment.

Renal cell carcinoma, a highly recurrent and metastatic malignancy. Drawing upon a decade-long expertise in managing recurrent cases, we advocate the adoption of Programmed Death-1 (PD-1) inhibitors in conjunction with Axitinib when monotherapy with Axitinib fails to restrain tumor metastasis, thereby empowering doctors with an efficacious treatment option.

Renal cell carcinoma is often difficult to diagnose early due to its nonspecific clinical presentation, which extends beyond the classic triad of flank pain, hematuria, and a flank mass. Recognizing alternative indicators, such as microscopic hematuria and lactic acidosis, can aid in early detection. A 77-year-old male with diabetes, varicose veins, and tobacco use presented with weakness, nausea, dyspnea, and poor appetite. He exhibited somnolence, confusion, transaminitis, elevated alkaline phosphatase, and severe lactic acidosis. Urinalysis revealed microscopic hematuria. Imaging showed bilateral pleural effusions and a right hepatic lesion. A computed tomography scan identified a large renal mass invading the renal vein, inferior vena cava, and right atrium. The patient developed deep vein thromboses and underwent radical nephrectomy, but succumbed postoperatively. This case highlights renal cell carcinoma's potential for atypical presentations, emphasizing the importance of early recognition and comprehensive diagnostic approaches to improve outcomes.

The initiation and progression of clear cell renal cell carcinoma (ccRCC) are closely linked to significant metabolic alterations. Specifically, lipid metabolism alterations and their association with the high invasiveness in ccRCC require further investigation. After conducting RNA-sequencing (RNA-seq), we discovered that Hydroxyacyl-CoA Dehydrogenase Trifunctional Multienzyme Complex Subunit Beta (HADHB) was significantly downregulated in the highly invasive ccRCC cell line. It was found that the expression of HADHB in ccRCC tumor tissues was lower than that in paracancer tissues, which is associated with poor patient prognosis. Subsequently, we confirmed that highly invasive ccRCC exhibited an increased lipid accumulation due to the suppression of mitochondrial fatty acid transport and enhanced conversion of fatty acids to triglycerides within cancer cells. Specifically, the downregulation of HADHB inhibited mitochondrial fatty acid β-oxidation (FAO) in cancer cells, leading to partial impairment of mitochondrial function and decreased ATP production. However, this trade-off involving the reduction of a high-yield ATP production conferred an advantage by reducing reactive oxygen species (ROS) generation within cancer cells, thereby protecting them from oxidative stress and enhancing their invasive potential. Furthermore, the downregulation of HADHB promoted epithelial-mesenchymal transition (EMT) and angiogenesis in cancer cells, accelerating the progression of ccRCC and endowing ccRCC cells with metastatic capabilities.

We aimed to estimate the effectiveness and safety of neoadjuvant systemic therapy in locally advanced renal tumor patients who undergo a nephrectomy in terms of survival, tumor response, and surgical feasibility.

We included clinical trials, quasi-experimental studies, and cohort studies providing data on the use of neoadjuvant systemic therapy in managing locally advanced renal cancer before surgery in adult patients. The primary outcomes were cancer-specific survival (CSS), overall survival (OS), progression-free survival (PFS), and disease-free survival (DFS). We performed a meta-analysis of proportions in R and assessed the risk of bias with the MINORS tool.

Nine studies were included for qualitative synthesis and seven for meta-analysis. All non-randomized studies assessed had a low risk of bias against the stated objective by clearly stating their purpose. Likewise, most studies had a low risk of bias in the consecutive inclusion of patients, contemporary groups, and equivalence. Change in tumor size ranged from -50% to +7.9%. Partial response was achieved in 26% (95% confidence interval 15-42).

Neoadjuvant therapy in locally advanced renal tumors ≥T3 or N1 has shown positive results regarding clinical tumor regression in about one-third of the patients. It is feasible and safe in this high-risk population.

Despite that incorporating antiangiogenic in combination with immune-checkpoint inhibitors as the standard first-line treatment for advanced clear cell renal cell cancer (ccRCC) yields promising outcomes, these regimens often lead to significant toxicity. However, a subgroup of patients has shown responsiveness to VEGFR tyrosine-kinase inhibitors (TKIs) in monotherapy, leading to the question of whether employing combination therapies can significantly enhance overall survival in all patients over monotherapy. Thus, we aim to identify gene expression signatures that can predict TKI response within subpopulations that might benefit from single-agent therapies, to minimize unnecessary exposure to combination therapies and their associated toxicities, as well as to discover new potential therapeutic targets to improve ccRCC treatment. Based on prior data, the androgen receptor (AR) might meet both conditions.

We evaluated the association between AR expression, assessed through NanoString® technology-derived mRNA counts, and the clinical outcomes of 98 ccRCC patients treated with first-line antiangiogenics and determined its association with other genes implicated in ccRCC tumorigenesis.

Higher AR-expression correlates significantly with better prognosis and survival based on the MSKCC risk score, and longer PFS. Furthermore, we have identified a gene set signature associated with AR-overexpression and several genes involved in angiogenesis and transcriptional targets of the hypoxia-inducible factor, a cornerstone of ccRCC.

AR-overexpression and its association with other genes could favor a transcriptomic signature set to aid in identifying patients suitable for TKI in monotherapy, rather than aggressive combinations, enhancing thus, precision and personalized therapeutic decisions.

This study aimed to empirically analyze gastrointestinal adverse events associated with Lenvatinib monotherapy and its combination with Pembrolizumab using FDA FAERS data (January 2015-December 2023), focusing on risk profiles, temporal patterns, and influencing factors. Proportional disproportionality analysis (ROR, PRR, BCPNN, EBGM) evaluated drug-AE associations. Kaplan-Meier curves characterized temporal distributions, while Wilcoxon rank-sum test compared median time-to-onset between regimens. Univariate logistic regression identified independent risk factors. A total of 291 severe gastrointestinal AEs reports were included. The gastrointestinal system had the most positive AE signals in both treatment groups. Perforation events showed strong positive signals in both regimens, while haemorrhage and fistula events were unique positive signals in the lenvatinib monotherapy group. In contrast, colitis and pancreatitis positive signals were more common in the combination therapy group. Most gastrointestinal AEs in both groups occurred within the first month of treatment. The monotherapy group had a significantly shorter median onset time than the combination therapy group (27 days vs. 38 days, P = 0.003). Logistic regression indicated that female sex (OR = 0.195, P = 0.022) and low-dose medication (OR = 0.240, P = 0.049) were independent protective factors for gastrointestinal AEs in the monotherapy group. This first comprehensive comparison reveals distinct gastrointestinal toxicity profiles: monotherapy predisposes to acute bleeding/fistulas, while combination therapy increases delayed tumor-related complications. Intensive monitoring during the first treatment month and gender/dosage-adjusted prevention strategies are recommended. These findings provide evidence-based insights for optimizing safety management of targeted-immunotherapy combinations.

Post-marketing surveillance focusing on hepatic function disorder was requested owing to its higher incidence in the pembrolizumab plus axitinib group than in the sunitinib group in KEYNOTE-426. We aimed to evaluate the prevalence and risk factors of adverse events (AEs) of hepatic function disorder in patients with unresectable/metastatic renal cell carcinoma (RCC) treated with pembrolizumab plus axitinib in real-world clinical practice in Japan.

Patients were observed for 9 months after starting treatment with pembrolizumab plus axitinib.

In total, 193 patients were included in the safety analysis set (median age, 70 years). Most patients did not have a history of hepatic function disorder before starting treatment (96.4%, 186/193). The median treatment period was 27.1 weeks. At the 9-month data cut-off, 62.2% (120/193) of patients discontinued treatment, the most common reason being any AE in 31.1% (60/193). The incidence of AEs of hepatic function disorder was 30.1% (58/193) for any grade and 15.0% (29/193) for grade ≥ 3. Most AEs of hepatic function disorder occurred within 3 months from starting treatment. AEs of hepatic function disorder were the reason for discontinuation of pembrolizumab in 9.3% (18/193) of patients; axitinib, 7.3% (14/193); and both pembrolizumab and axitinib, 5.2% (10/193). No background factors were identified as being associated with the occurrence of AEs of hepatic function disorder.

There were no new safety signals for AEs of hepatic function disorder, and the incidence was consistent with that reported in KEYNOTE-426, in Japanese patients with radically unresectable/metastatic RCC treated with pembrolizumab plus axitinib.

The RAS signaling pathway is one of the most commonly dysregulated pathways in urological cancers. This pathway can be regulated by RASGAPs, which catalyze the hydrolysis of RAS-GTP to RAS-GDP. As such, the loss of RASGAPs can promote the activation of the RAS signaling pathway. Dysregulation of RASGAPs significantly contributes to the progression of urological cancers, including prostate cancer, bladder cancer, and renal cell carcinoma. Furthermore, alterations in RASGAP expression may influence sensitivity to chemotherapy, radiotherapy, and targeted therapies, suggesting their potential as therapeutic targets. Despite the challenges involved, a deeper understanding of the complexity of the RAS signaling network, along with the evolution of personalized medicine, holds promise for delivering more precise and effective treatment options targeting RASGAPs in urological cancers.

In the development of several cancers, the Forkhead Box M1 (FOXM1) is crucial. The relationship between the immune system and FOXM1 in renal cell carcinoma (ccRCC), which has been verified by bulk RNA sequencing and scRNA sequencing, is the primary subject of this research.

Publicly available data related to FOXM1 and ccRCC were extracted from The Cancer Genome Atlas (TCGA) database. The impact of FOXM1 on the prognosis of ccRCC was examined using Cox regression analysis. Results were verified by immunohistochemistry and quantitative real-time PCR (qRT-PCR). Additionally, single-cell sequencing data were analyzed.

When compared to para-carcinoma tissues, the expression of FOXM1 was considerably higher in ccRCC tissues. Patients with elevated FOXM1 expression had lower survival rates. FOXM1 may be a standalone prognostic factor for ccRCC, according to results of univariate and multivariate Cox regression studies. Reduced FOXM1 expression was linked to higher immunotherapy sensitivity, according to immunocorrelation analysis. This suggests FOXM1 may mediate immunotherapy resistance in ccRCC. Additionally, FOXM1 showed strong associations with tumor mutation load, microsatellite instability, and antitumor immunity. These results imply FOXM1 may regulate antitumor immunity in the ccRCC microenvironment. Consistent results from immunohistochemistry, PCR, and single-cell RNA sequencing confirmed upregulated FOXM1 expression in ccRCC.

According to the findings, FOXM1 might be used as a stand-alone prognostic biomarker for ccRCC. Moreover, FOXM1 has exhibited robust correlations with microsatellite instability, tumor mutation burden, immune response, and immunotherapy efficacy. FOXM1 may promote ccRCC pathogenesis partly by suppressing antitumor immunity and mediating immunotherapy resistance.

Renal cell carcinoma (RCC) presents a significant diagnostic challenge, particularly in small renal masses. The search for non-invasive screening methods and biomarkers has directed research toward liquid biopsy, which focuses on microRNAs (miRNAs), exosomes, and circulating tumor cells (CTCs). miRNAs are small non-coding RNA molecules that show considerable dysregulation in RCC, and they have potential for both diagnostic and prognostic applications. Research has highlighted their utility on biofluids, such as plasma, serum, and urine, in detecting RCC and characterizing its subtypes. Promising miRNA signatures have been associated with overall survival, suggesting their potential importance in the management of RCC. Exosomes, which carry a variety of molecular components, including miRNAs, are emerging as valuable biomarkers, whereas CTCs, released from primary tumors into the bloodstream, provide critical information on cancer progression. However, translation of these findings into clinical practice requires additional validation and standardization through large-scale studies and robust evidence. Although there are currently no approved diagnostic tests for RCC, the future potential of liquid biopsy in monitoring, treatment decision-making, and outcome prediction in patients with this disease is significant. This review examined and discussed recent developments in liquid biopsy for RCC, assessing both the strengths and limitations of these approaches for managing this disease.

The introduction of multi-targeted tyrosine kinase inhibitors (MTKIs) such as axitinib, lenvatinib, sorafenib, and sunitinib has greatly broadened the available treatment options for Renal Cell Carcinoma (RCC). The study aims to compare the nature of the adverse reactions associated with these four MTKIs to identify which medication poses the least risk for personalized patient management, thus enabling more accurate clinical drug oversight.

Employing a retrospective descriptive analysis methodology, this research concentrated on four commercially available MTKIs. Reports pertaining to these medications were sourced from the WHO-VigiAccess database. The data gathering process involved collecting comprehensive information on various parameters, such as age demographics, gender, and the geographical distribution of patients associated with the ADR reports. Furthermore, the study explored disease systems and symptoms that were documented alongside the adverse reactions, as outlined in the annual ADR reports produced by the WHO. To assess the relationship between these four MTKIs and the linked AEs, both the Proportional Reporting Ratio (PRR) and the Reported Odds Ratio (ROR) were utilized.

At the time of the search, a total of 123,818 AEs associated with the four MTKIs had been documented in the VigiAccess database. The common ADRs for these four MTKIs include diarrhoea, fatigue, death, hypertension, nausea, asthenia, weight decreased, and vomiting. Gastrointestinal disorders and general disorders and administration site conditions emerged as the SOCs with the highest number of adverse signals, both ranking first in terms of frequency. The elevated ROR (1.08) and PRR (1.06) values associated with gastrointestinal disorders in patients treated with sorafenib suggest a higher incidence of such adverse events compared to those observed with axitinib, lenvatinib, and sunitinib.

Recent comparative observational research suggests that the ADR reports submitted to the WHO and the FDA for these medications highlight both common and specific ADRs. It is essential for clinical practitioners to develop personalized treatment strategies that consider the adverse effects linked to different medications, alongside the unique circumstances of their patients, thus encouraging the responsible use of these MTKIs.

Histone deacetylases (HDACs) have emerged as key regulators in the pathogenesis of various kidney diseases. This review explores recent advancements in HDAC research, focusing on their role in kidney development and their critical involvement in the progression of chronic kidney disease (CKD), acute kidney injury (AKI), autosomal dominant polycystic kidney disease (ADPKD), and diabetic kidney disease (DKD). It also discusses the therapeutic potential of HDAC inhibitors in treating these conditions. Various HDAC inhibitors have shown promise by targeting specific HDAC isoforms and modulating a range of biological pathways. Their protective effects include modulation of apoptosis, autophagy, inflammation, and fibrosis, underscoring their broad therapeutic potential for kidney diseases. However, further research is essential to improve the selectivity of HDAC inhibitors, minimize toxicity, overcome drug resistance, and enhance their pharmacokinetic properties. This review offers insights to guide future research and prevention strategies for kidney disease management.

Current primary liver cancer therapies, including sorafenib and transarterial chemoembolization, face significant limitations due to chemoresistance caused by impaired drug uptake, altered metabolism, and other genetic modulations. These challenges contribute to relapse rates of 50-80% within five years. The need for improved treatment strategies (adjuvant therapy, unsatisfactory enhanced permeability and retention (EPR) effect) has driven research into advanced drug delivery systems, including targeted nanoparticles, biomaterials, and combinatory approaches. Therefore, this review evaluates recent advancements in primary liver cancer pharmacotherapy, focusing on the potential of drug delivery systems for sorafenib and its derivatives. Approaches such as leveraging Kupffer cells for tumor migration or utilizing smaller NPs for inter-/intracellular delivery, address EPR limitations. Biomaterials and targeted therapies focusing on targeting have demonstrated effectiveness in increasing tumor-specific delivery, but clinical evidence remains limited. Combination therapies have emerged as an interesting solution to overcoming chemoresistance or to broadening therapeutic functionality. Biomimetic delivery systems, employing blood cells or exosomes, provide methods for targeting tumors, preventing metastasis, and strengthening immune responses. However, significant differences between preclinical models and human physiology remain a barrier to translating these findings into clinical success. Future research must focus on the development of adjuvant therapy and refining drug delivery systems to overcome the limitations of tumor heterogeneity and low drug accumulation.

Sin3A-associated protein 30 (SAP30) is a crucial component of the SIN/HDAC histone deacetylase complex and acts as a scaffold that facilitates target gene binding. SAP30 is highly expressed in various tumours; however, its role in renal cell carcinoma (RCC) remains unclear. In our study, we observed the upregulation of SAP30 in clear cell renal cell carcinoma (ccRCC) tissues, and its elevated expression was correlated with a poor prognosis. Previous research has suggested that SAP30 may influence the growth, proliferation, and apoptosis of RCC cells. Gene Ontology (GO) analysis of the downstream regulatory targets of SAP30 revealed that SAP30 suppressed the expression of MT1G, a protein that binds to p53. Mechanistically, SAP30 inhibited MT1G transcription, thereby impairing the function of MT1G in delivering zinc ions to p53, which diminished p53 activity. Moreover, reduced MT1G levels attenuated the inhibitory effect of MT1G on MDM2, further destabilizing p53. Consequently, this cascade promoted RCC progression. In conclusion, our findings indicate that SAP30 inhibits the p53 pathway through MT1G suppression, suggesting that SAP30 and MT1G are potential prognostic markers and therapeutic targets for RCC.

Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer that often displays resistance to conventional cancer therapies, including chemotherapy and radiation therapy. Targeted treatments, including immunotherapies and small molecular inhibitors, have been associated with improved outcomes. However, variations in the patient response and the development of resistance suggest that more models that better recapitulate the pathogenesis and metastatic mechanisms of ccRCC are required to improve our understanding and disease management. Here, we examined the transcriptional landscapes of in vitro cell culture as well as in vivo orthotopic and metastatic NOD/SCID-γ mouse models of ccRCC using a single patient-derived RCC243 cell line to allow unambiguous comparison between models. In our mouse model assays, RCC243 cells formed metastatic tumors, and all tumors retained clear cell morphology irrespective of model type. Notably, gene expression profiles differed markedly between the RCC243 tumor models-cell culture, orthotopic tumors, and metastatic tumors-suggesting an impact of the experimental model system and whether the tumor was orthotopic or metastatic. Furthermore, we found conserved prognostic markers between RCC243 tumor models and human ccRCC patient datasets, and genes upregulated in metastatic RCC243 were associated with worse patient outcomes.

Renal cell carcinoma (RCC) is the one of the most fatal and frequent form of urological malignancy worldwide. The von Hippel-Lindau (VHL) tumour suppressor gene is a critical component of the VHL-Cullin2-ElonginB/C (VCB) complex that regulates the ubiquitin-mediated proteasomal degradation of proteins with mutations consistently associated with the development of clear cell renal cell carcinoma (ccRCC). Despite extensive investigations conducted worldwide, there is a notable lack of data concerning VHL mutations in sporadic ccRCC patients from India. Our study aimed to investigate the sporadic VHL mutations within the tumours of 210 ccRCC patients without a familial history of VHL disease. We extracted genomic DNA from tumour and adjacent normal tissues, PCR amplified and sequenced the VHL gene. In silico tools were used assess the damaging potential of missense variants on pVHL structure and stability. Protein-protein docking and protein flexibility molecular docking simulation study were employed to study the interaction between wild-type and mutated VHL models with Elongin C. Sequence analysis revealed seven novel missense mutations in patient tumour tissues p.(Val170Phe), p.(Arg69Cys), p.(Phe76Leu), p.(Glu173Asp), p.(Leu201Val), p.(His208Leu), p.(Arg205Pro). I-Mutant 2.0 indicated these mutations reduced pVHL stability (ΔΔG < -0.5 kcal/mol). Protein Flexibility-Molecular Dynamic (MD) Simulation study indicated that mutations weaken the interaction of VHL with Elongin C, with V170F showing the most significant reduction in binding quality and stability. In conclusion, this study introduces novel genetic data from an understudied population and highlights the impact of VHL mutations on its interaction with Elongin C. These findings contribute to our understanding of the molecular basis of VHL-related pathologies and may guide future therapeutic strategies targeting these interactions.

Splicing is often dysregulated in cancer, leading to alterations in the expression of canonical and alternatively spliced isoforms. We used the multiplexed arrays sequencing (MAS-seq) protocol of PacBio to sequence full-length transcripts in patient-derived organoid (PDO) cells of clear cell renal cell carcinoma (ccRCC). The sequencing revealed a heterogeneous dysregulation of splicing across 2599 single ccRCC cells. The majority of novel transcripts could be removed with stringent filtering criteria. The remaining 31,531 transcripts (36.6% of the 86,182 detected transcripts on average) were previously uncharacterized. In contrast to known transcripts, many of the novel transcripts have cell-specific expression. Novel transcripts common to ccRCC cells belong to genes involved in ccRCC-related pathways, such as hypoxia and oxidative phosphorylation. A novel transcript of the ccRCC-related gene nicotinamide N-methyltransferase is validated using PCR. Moreover, >50% of novel transcripts possess a predicted complete protein-coding open reading frame. An analysis of the most dominant transcript-switching events between ccRCC and non-ccRCC cells shows many switching events that are cell- and sample-specific, underscoring the heterogeneity of alternative splicing events in ccRCC. Overall, our study elucidates the intricate transcriptomic architecture of ccRCC, underlying its aggressive phenotype and providing insights into its molecular complexity.

The management of metastatic renal cell carcinoma (mRCC) has advanced with recent therapies, yet optimizing treatment remains challenging due to disease heterogeneity and the growing number of options. Integrating systemic and local treatments requires a multidisciplinary approach to improve outcomes.

This review summarizes recent developments in treatment for mRCC. Upfront immuno-oncology (IO)-based combinations have improved survival, though concerns about overtreatment and toxicity persist. While the role of cytoreductive nephrectomy (CN) has declined to some extent, it may still benefit well-selected patients. Metastasis-directed therapies, including metastasectomy and stereotactic radiotherapy, provide prognostic value, particularly for oligometastatic lesions or brain metastases. Comprehensive genomic profiling (CGP) holds promise for personalized treatment but is currently limited by the lack of actionable mutations and predictive biomarkers.

A personalized, multimodal approach is essential for optimizing mRCC management. Careful patient selection is key to balancing the benefits of treatment with the risks of toxicity. While CN and metastasis-directed therapies remain useful in select cases, advancing individualized care requires the development of validated biomarkers and broader application of CGP.

Background: Immunotherapy has revolutionized cancer treatment and holds great potential for them, including metastatic clear cell renal cell carcinoma (ccRCC). However, immune resistance remains a major obstacle, limiting its efficacy and durability. Understanding the mechanisms of immune tolerance in the tumor microenvironment (TME) is pivotal for overcoming these challenges and enhancing therapeutic outcomes. Methods: Over 2000 samples, including a real-world cohort of 230 advanced ccRCC patients treated with immune checkpoint blockade (ICB) were analyzed. Single-cell RNA sequencing data from 13 tumor regions were categorized into ICB-exposed, ICB-resistant, and ICB-responsive groups. Multiple robust algorithms and multiplex immunofluorescence were used to explore TME composition and macrophage heterogeneity. Spatial communication dynamics were further investigated. In vitro experiments were performed to evaluate the impact of SPP1 on 786-O and 769-P cells. Co-culture experiments with THP-1-derived macrophages, followed by Western blot, flow cytometry, and functional assays, were performed to investigate SPP1-mediated macrophage polarization and its impact on tumor progression. Results: The results revealed an elevated presence of Apolipoprotein E (APOE)+ macrophages in ICB-resistant ccRCC. Notably, higher APOE+ macrophage proportion indicated shorter prognosis and worse response to ICB (P < 0.001). Elevated expression of CCAAT Enhancer Binding Protein Delta (CEBPD) was markedly linked to several immunosuppressive pathways, hindering T cell recruitment, promoting exhaustion, ultimately diminishing poorer prognosis and worse ICB efficacy. Meanwhile, upregulated Secreted Phosphoprotein 1 (SPP1) significantly enhances the proliferation, clonal formation, and migration of ccRCC cells. Tumor-derived SPP1. Additionally, SPP1 signaling from malignant cells appeared to recruit APOE+ macrophages to tumor margins, and promotes macrophage polarization into APOE+ M2-like macrophages. In the vicinity of the tumor, these APOE+ macrophages shape immunosuppressive TME by releasing abundant TGF-β signals, limiting anti-tumor effector T cells activity in ICB-resistant tumors, and contributing to tumor progression. Conclusion: This study reveals the critical role of APOE+ macrophages in promoting immune suppression and resistance to ICB therapy in ccRCC. By promoting T cell exhaustion and immunosuppressive signaling, particularly via localized TGF-β, these spatially segregated macrophages undermine treatment efficacy. Targeting APOE+ macrophages, especially in conjunction with ICB, presents a promising strategy to overcome immune resistance and enhance outcomes for ccRCC patients.

The most notable progress in renal clear cell carcinoma (ccRCC) in the past decades is the introduction of drugs targeting the VHL-HIF signaling pathway-associated angiogenesis. However, mechanisms underlying the development of VHL mutation-independent ccRCC are unclear. Here we provide evidence that the disrupted Hippo-YAP signaling contributes to the development of ccRCC independent of VHL alteration. We found that YAP1 and its primary target genes are frequently upregulated in ccRCC and the upregulation of these genes is associated with unfavorable patient outcomes. Research results derived from our in vitro and in vivo experimental models demonstrated that, under normoxic conditions, hyperactivated YAP1 drives the expression of FGFs to stimulate the proliferation of tumor and tumor-associated endothelial cells in an autocrine/paracrine manner. When rapidly growing cancer cells create a hypoxic environment, hyperactivated YAP1 in cancer cells induces the production of VEGF, which promotes the angiogenesis of tumor-associated endothelial cells, leading to improved tumor microenvironment and continuous tumor growth. Our study indicates that hyperactivated YAP1 is essential for maintaining ccRCC progression, and targeting the dual role of hyperactivated YAP1 represents a novel strategy to improve renal carcinoma therapy.