Search Results (799)

Background: Cytochrome P450 2J2 (CYP2J2) has been implicated in tumor biology, but its expression pattern and clinical significance in prostate and renal cancers remain poorly characterized. Methods: Commercially available tissue microarrays containing 208 renal and 121 prostate tissue specimens were used for immunohistochemical (IHC) characterization of CYP2J2 protein expression. We performed transcriptomic analysis and examined correlations with clinicopathological features and survival using the OncoDB 2.0 platform. Results: CYP2J2 immunoreactivity was mainly cytoplasmic, with minimal protein expression in both cancers. We identified positive staining in 7/100 (7.0%) prostate adenocarcinomas and 2/192 (1.0%) clear cell renal cell carcinoma (ccRCC) specimens, with negative expression in corresponding normal tissues. We detected no significant associations between protein expression and clinicopathological features in either cohort (all p > 0.05). In contrast, transcriptomic analysis revealed elevated CYP2J2 mRNA expression in both malignancies, with a slight increase in prostate adenocarcinoma (log₂ fold change = 1.10) and marked overexpression in ccRCC (log₂ fold change = 5.24) compared with normal tissues. We observed significant associations between CYP2J2 mRNA expression and pathological T stage in prostate adenocarcinoma (p = 0.0019) and pathological M stage in ccRCC (p = 0.0079). Moreover, higher CYP2J2 mRNA expression was associated with longer overall survival in ccRCC (HR = 0.64, 95% CI: 0.47–0.86; log-rank p = 0.0029) but not in prostate adenocarcinoma; however, these findings remain exploratory and do not establish independent prognostic value. Conclusions: Despite elevated transcript expression, CYP2J2 protein expression was infrequent in prostate adenocarcinoma and ccRCC, suggesting limited clinicopathological relevance and warranting further investigation using functional techniques. Full article

Clear cell renal cell carcinoma (ccRCC) is the most common and aggressive type of renal cell carcinoma (RCC), representing approximately 80% of cases globally. Despite improved diagnosis and therapy, treatment of aggressive or metastatic ccRCC remains challenging due to acquisition of primary or secondary resistance. Among the dysregulated signaling mechanisms identified in ccRCC, the mechanistic target of rapamycin (mTOR) and the nuclear factor kappa light-chain enhancer of activated B cells (NF-κB) pathways play central roles in regulating various biological functions such as metabolism, inflammation, tumor growth, and survival. However, the molecular crosstalk between mTOR and NF-κB signaling in ccRCC progression and therapeutic resistance remains poorly understood. Therefore, in our current study, we aimed to investigate the interplay between mTOR and NF-κB signaling in ccRCC. We analyzed tumor tissue samples from human ccRCC patients. For validation of mTOR and NF-κB signaling, we used two human ccRCC cell lines, A498 and 786-O. Using pharmacological inhibitors of mTOR and IKK/NF-κB signaling, Torin-1 and MLN120B, respectively, we assessed the functional relationship between these two pathways employing immunoblotting, EdU-based immunocytochemistry, and functional assays. Our findings reveal that both mTOR and NF-κB pathways are aberrantly activated in human ccRCC tissues. Phosphorylation of IκBα, S6, and 4E-BP1 was increased compared with matched adjacent control tissue. In A498 and 786-O cells, pharmacological inhibition of mTOR or IKK/NF-κB altered key readouts of the reciprocal pathway, including AKT, S6, 4E-BP1, IκBα and p65 phosphorylation. Both inhibitors reduced cell number and EdU incorporation, with stronger anti-proliferative effects observed after Torin-1 treatment. Pharmacological inhibition of either pathway altered key readouts of the other pathway, supporting a reciprocal functional association between mTOR- and NF-κB-associated signaling in the ccRCC models analyzed. Our findings support a functional association between mTOR- and NF-κB-associated signaling in the ccRCC models and provide a rationale for further mechanistic studies evaluating combined pathway modulation. Full article

This review summarises current evidence on renal cell carcinoma (RCC) with sarcomatoid dedifferentiation (sRCC), with an emphasis on diagnosis, prognostic stratification, and treatment. Sarcomatoid dedifferentiation is characterised by high-grade spindle cell morphology, occurs in 2–26% of all RCC patients, predominantly in the clear cell subtype (~70%), and is WHO/ISUP grade 4 regardless of extent of involvement. Thus, sRCC represents a pathological transformation rather than a distinct entity. Diagnosis requires biopsy or nephrectomy; immunohistochemical (IHC) retention of PAX8, cytokeratins, and vimentin alongside loss of subtype-specific markers distinguishes sRCC from primary renal sarcoma. On CT, sRCC typically presents as a large, heterogeneous mass with extensive necrosis; 18F-FDG PET/CT carries independent prognostic value, though no feature is pathognomonic. Sarcomatoid features are approximately five times more prevalent in patients with metastatic vs. localised disease (~20 vs. ~4%), and their identification should prompt risk stratification. Median overall survival (OS) in metastatic sRCC is 5.9–13.3 months, though recent data suggest improvement with novel therapies. Sarcomatoid dedifferentiation is characterised by enrichment of alterations in TP53, BAP1, CDKN2A/B, and NF2 on a background of founder RCC mutations, generating an immune-inflamed tumour microenvironment with elevated CD8+ T cell infiltration and PD-L1 expression that may underpin the heightened sensitivity of sRCC to immune checkpoint inhibitors (ICI). Surgery remains the cornerstone in localised disease, although recurrence rates approach 80% within two years. Adjuvant pembrolizumab significantly improved disease-free survival in high-risk localised RCC with sarcomatoid features (KEYNOTE-564; NCT03142334). In the metastatic setting, nivolumab plus ipilimumab and pembrolizumab plus axitinib are preferred first-line regimens. Full article

Background: Renal cell carcinomas (RCCs) represent neoplasms with variable biological behaviour, some of which remain difficult to classify within the current diagnostic framework. Clear cell papillary renal cell tumor (CCPRCT) is now recognised as an indolent entity, whereas RCC with fibromyomatous stroma (RCCFMS) remains a provisional subtype with partially overlapping morphological features. Methods: We analysed a multifocal RCC with clear cell morphology and prominent fibromyomatous stroma via whole-genome and RNA sequencing. The obtained molecular profile was compared with The Cancer Genome Atlas (TCGA) pan-cancer dataset, which includes 885 RCC cases, and histological re-evaluation of 10 identified similar cases was performed. Transcriptional data were mined for potential markers, which were validated in an independent cohort. Results: The 10 TCGA cases with similar transcriptomic features were characterised by diploid genomes, absence of recurrent chromosomal alterations, and lack of VHL mutations. Reduced VHL mRNA expression was observed, with increased methylation at selected CpG sites consistent with possible epigenetic down-regulation. Diagnostic variability was identified during histological re-evaluation of the 10 similar cases by three urological pathologists. Differential expression analysis highlighted cytokeratin 17 (CK17) and collagen 17A1 (COL17A1) as candidate markers. Immunohistochemical evaluation in a small (n = 6) independent CCPRCT cohort demonstrated expression of both markers, whereas tissue microarrays from 257 clear cell and 68 papillary RCC cases were found to be negative. Conclusions: These findings suggest that a subset of renal tumors with overlapping morphological features of CCPRCT and RCCFMS may share common molecular characteristics. CK17 and COL17A1 emerged as candidate markers for recognising these tumors, although their diagnostic sensitivity and specificity require validation across a broader spectrum of renal neoplasms. These observations are exploratory and hypothesis-generating, and further studies in large, well-characterised cohorts are required to clarify the biological and diagnostic significance of this subgroup. Full article

Background: Telomerase is a ribonucleic multimeric reverse transcriptase complex protecting the chromosomal ends from erosion and thereby from cellular senescence. The prognostic value of the components of this complex and their interrelationships with the immune system are not well understood. Objectives: We aimed to examine 15 telomerase-related genes across 7489 tumor samples from the TCGA database. Methods: The mRNA expression of these genes was analyzed using Kaplan–Meier statistics and hierarchical clustering analyses, alone or in combination with tumor infiltration counts for 11 immune cell types. As an additional analysis, univariable and multivariable Cox regression analyses have been performed. Results: Thirteen of 21 tumor types showed significant associations between gene expression in tumors and survival times of patients. Most gene correlations were found in hepatocellular carcinoma and renal clear cell carcinoma. In hepatocellular carcinoma, a high expression of DKC1, NHP2, GAR1, WRAP53, and ACD was associated with shorter survival. In renal clear cell carcinoma, TERT, DKC1, and PARN correlated with shorter survival, and NAF1, TERF2, POT1, and TINF2 with longer survival. DKC1 was the only gene significantly associated with poor prognosis in both tumor types. The telomerase-related genes correlated with patterns of immune cell infiltration, which influenced the survival of patients. The associations of mutation burden and neoantigen load with survival varied depending on the gene and patient groups. In renal clear cell carcinoma, TERT, DKC1, and PARN showed strong interactions with immune cell infiltration and neoantigen load. Conclusions: The combination of telomerase-related gene expression and immune-cell infiltration was associated with overall survival in hepatocellular carcinoma and renal clear cell carcinoma and warrants further evaluation as prognostic markers. Full article

Background/Objectives: Accurate prognostic stratification after nephrectomy for clear cell renal carcinoma (ccRCC) remains challenging. Traditional models often lack the intuitive clinical application or the ability to handle non-linear interactions between variables. We aimed to develop and internally validate a decision tree-based model to predict cancer-specific survival in patients with ccRCC following nephrectomy. Methods: We analyzed 79,526 patients with ccRCC who underwent nephrectomy from the SEER database (2012–2018). Patients were randomized into development (2/3) and validation (1/3) cohorts. A conditional inference tree was constructed to predict cancer-specific survival. Multiple imputation by chained equations was used to handle missing data. Discriminatory ability was assessed using the C-index. Net clinical benefit was evaluated with decision curve analysis. The model was evaluated using CHARMS and PROBAST. Results: A decision tree with 15 risk groups is presented, further classified into high-, intermediate-, and low-risk categories according to observed median survival. The final predictors were tumor localization, tumor grade, TNM stage, age, and sarcomatoid differentiation. The model demonstrated excellent discriminatory performance, with a C-index of 0.846 (95% CI: 0.834–0.847). PROBAST assessment showed low risk of bias and low concern regarding applicability. Conclusions: The use of decision trees provides an interpretable alternative to conventional regression-based models. Three main risk categories and 15 subgroups are proposed based on tumor localization, tumor grade, TNM stage, age, and sarcomatoid differentiation. Our model demonstrates good applicability and a low risk of bias according to PROBAST guidelines; however, external validation in independent cohorts is required prior to clinical implementation. Full article

Background: Sunitinib remains an important VEGFR-targeted therapy for advanced clear cell renal cell carcinoma (ccRCC), but acquired resistance frequently limits its clinical benefit. The molecular mechanisms underlying sunitinib resistance remain insufficiently understood. Methods: Sunitinib-resistant ccRCC models were generated by serial in vivo selection using Caki-1 and 786-O xenografts. Transcriptomic profiling, integration with GSE76068, and siRNA-based screening were performed to identify candidate resistance drivers. DERL3 expression and function were validated using qRT-PCR, Western blot, immunohistochemistry, gain- and loss-of-function assays, xenograft models, and mechanistic analyses of endoplasmic reticulum stress, ROS, and apoptosis. Results: Serial in vivo selection established stable sunitinib-resistant Caki-1-SR and 786-O-SR cells with markedly increased IC50 values. Integrated transcriptomic analysis identified six consistently upregulated genes in resistant models and GSE76068, among which DERL3 knockdown most strongly restored sunitinib sensitivity. DERL3 was upregulated in resistant ccRCC cells and clinical resistant specimens. High intratumoral DERL3 expression was associated with poor response to neoadjuvant sunitinib and shorter progression-free and overall survival. Functionally, DERL3 overexpression increased sunitinib resistance in vitro and in vivo, whereas DERL3 silencing restored drug sensitivity. Mechanistically, DERL3 depletion activated pro-apoptotic endoplasmic reticulum stress, increased ROS accumulation, and enhanced caspase-dependent apoptosis. Suppression of endoplasmic reticulum stress reduced ROS generation and apoptosis induced by DERL3 knockdown. In resistant xenografts, DERL3-targeted inhibition enhanced the antitumor efficacy of sunitinib. Conclusions: DERL3 is a clinically relevant driver of acquired sunitinib resistance in ccRCC. Targeting DERL3 may restore sunitinib sensitivity by reactivating pro-apoptotic endoplasmic reticulum stress and ROS-dependent apoptosis. Full article

Introduction: The “obesity paradox” describes the observed association between improved cancer-specific (CSS) and overall (OS) survival observed among obese (BMI ≥ 30 kg/m²) patients with RCC. Prior studies have reported lower stage/grade tumors among obese patients to explain this. This study aimed to evaluate subcutaneous (SFA) and visceral fat area (VFA) associations with CSS, OS, tumor stage and grade among patients with non-metastatic clear cell RCC. Methods: Following IRB approval, patients undergoing nephrectomy for clear cell RCC between 2000 and 2023 were screened for inclusion. Eligible patients were those with non-metastatic disease and available preoperative imaging within 90 days of surgery. SFA and VFA were determined using mid-L3 imaging and standardized Hounsfield Unit thresholds. Multivariable Cox models evaluated factors associated with 5-year CSS and OS, and multivariable logistic regression models evaluated associations with pathologic stage (pT) 3–4 and Fuhrman grade 3–4 disease. Results: 400 patients were included. Higher SFA quartiles were independently associated with improved CSS (Q3 HR 0.21, p = 0.029; Q4 HR 0.24, p = 0.042) and OS (Q2-Q4 HR range 0.35–0.52, all p < 0.05) compared to Q1. VFA was not independently associated with OS and showed only an isolated association with CSS in the third quartile (HR 2.95, p = 0.041). Neither SFA nor VFA were independently associated with RCC stage or grade. Conclusions: Greater subcutaneous adiposity was associated with improved 5-year CSS/OS, whereas visceral adiposity did not demonstrate consistent associations with survival outcomes. These findings refine the obesity paradox and reflect the importance of fat distribution as a more specific risk factor than weight-based measures such as BMI alone. Full article

Background/Objectives: Evaluation of renal tumour masses relies on conventional imaging, which cannot reliably characterise the histopathological type, and no validated blood-based diagnostic marker is available for renal cell carcinoma. The cfDNA integrity index, the ratio of long to short circulating cell-free DNA (cfDNA) fragments, may reflect the necrotic origin of tumour-derived DNA and is a candidate qualitative marker of malignancy. This exploratory, single-centre case–control study assessed the preoperative plasma cfDNA integrity index in patients with clear cell renal cell carcinoma (ccRCC). Methods: Plasma concentrations of 90 bp and 222 bp cfDNA fragments were measured by quantitative real-time PCR (qPCR) in 46 patients with histopathologically confirmed ccRCC (before surgery) and 17 healthy volunteers; the two groups were a convenience sample, were not matched, and differed in age and body-mass index. The cfDNA integrity index was defined as the ratio of the 222 bp to the 90 bp fragment concentration. Results: The cfDNA integrity index was higher in patients with ccRCC than in controls (median 0.28 vs. 0.15; p < 0.001, Mann–Whitney test) and rose progressively across healthy, non-metastatic (M0) and metastatic (M1) groups (p < 0.001, Kruskal–Wallis test; M0 vs. M1 p = 0.004). In unadjusted ROC analysis, both the integrity index (AUC 0.83, 95% CI 0.72–0.94) and its long 222 bp fragment component (AUC 0.93) discriminated patients with ccRCC from healthy volunteers, and the index separated metastatic from non-metastatic disease with an AUC of 0.79 (95% CI 0.64–0.88). The index was higher in high-grade (Fuhrman G3 + G4) tumours (p = 0.04) and in tumours with lymphovascular invasion (p < 0.001), and correlated with primary-tumour diameter. Conclusions: In this exploratory cohort, the preoperative plasma cfDNA integrity index was higher in patients with ccRCC than in healthy volunteers and was associated with several adverse pathological features; these findings require confirmation in larger, matched studies that include benign renal masses before any diagnostic role can be claimed. Full article

Background: Clear cell renal cell carcinoma (ccRCC) is characterized by marked molecular heterogeneity, aggressive clinical behavior, and prominent angiogenesis, highlighting the need to better understand the functional regulators underlying tumor progression and vascular remodeling. OTOF has previously been reported as a prognostically relevant gene in ccRCC; however, its biological function and potential involvement in tumor angiogenesis remain unclear. Methods: In the present study, we investigated the biological and pro-angiogenic roles of OTOF and explored the signaling pathways potentially involved. Results: Analysis of the TCGA-KIRC cohort confirmed that elevated OTOF expression was associated with unfavorable clinical outcomes. Functional experiments demonstrated that OTOF knockdown suppressed ccRCC cell proliferation, migration, and invasion and inhibited xenograft tumor growth. OTOF depletion also reduced intratumoral vascularization and impaired the ability of ccRCC cell-conditioned medium to promote HUVEC tube formation. Mechanistically, OTOF knockdown decreased VEGFA levels and was accompanied by reduced AKT phosphorylation and suppression of downstream HIF/VEGFA signaling. Pharmacological modulation of AKT signaling and VEGFA add-back experiments further supported the functional involvement of the AKT/HIF/VEGFA pathway in OTOF-associated angiogenesis. Conclusions: These findings extend previous observations regarding the prognostic relevance of OTOF by providing functional and mechanistic evidence that OTOF contributes to ccRCC progression and angiogenesis, at least in part, through AKT-dependent HIF/VEGFA signaling. Full article

Here, we report the identification of a previously unrecognized population of tumor-induced podoplanin-positive (PDPN⁺) cells in clear-cell renal cell carcinoma (ccRCC) that exhibit features of under-differentiated lymphatic endothelial cells (LECs). These PDPN⁺ cells lack a complete repertoire of canonical LEC markers, including VE-cadherin, LYVE1, and VEGFR3, and fail to form functional lymphatic vessels, indicating a dysplastic phenotype. We termed these cells dysLECs and found that these cells are induced by BMP10 produced specifically by tumor cells. In turn, dysLECs secrete CXCL13, which promotes tumor cell proliferation and metastasis. Ligand-receptor analyses revealed a highly tumor-specific reciprocal signaling circuit: kidney tubule cells deficient in the von Hippel-Lindau (VHL) tumor suppressor gene uniquely express BMP10, a TGF-β family cytokine, whereas its receptor ALK1 is restricted to dysLECs; conversely, dysLECs produce CXCL13, while VHL mutant kidney tubule cells uniquely express its receptor, CXCR5. Pharmacological inhibition of ALK1 reduced CXCL13 production and suppressed the hyperplastic phenotype of VHL mutant tumor cells in vivo, whereas BMP10 neutralization inhibited tumor growth and metastasis in an orthotopic ccRCC xenograft model. Collectively, these findings identify a dysplastic population of PDPN⁺ lymphatic-like endothelial cells and define a tumor-specific BMP10-CXCL13 signaling axis that drives ccRCC progression, uncovering a previously unrecognized therapeutic vulnerability in this disease. Full article

Background/Objectives: Clear cell renal cell carcinoma (ccRCC) is frequently vascular and immune-infiltrated, yet durable responses to immune checkpoint blockade remain limited. This suggests that immune resistance may reflect tumor microenvironmental organization and mechanotransduction state rather than immune infiltration alone. We aimed to determine whether matrix reorganization and branch-specific integrin mechanosensing define immune-regulatory states in ccRCC, with particular attention to adenosine-associated immune resistance. Methods: We performed an integrative computational analysis of TCGA-KIRC bulk RNA-sequencing, clinical, survival, immune feature, and reverse-phase protein array data. Matrix- and mechanobiology-related programs were quantified using ssGSEA, compact z-score-based signatures, and principal component-based sensitivity analyses. Immune-regulatory programs, CAF and ECM scores, FAK/SRC activation features, and MINER-inferred transcriptional regulons were integrated using stage association, correlation, partial correlation, variance partitioning, survival, and transcriptional state analyses. Results: Matrix-centered transcriptional programs were the dominant stage-associated mechanobiology signal in ccRCC, including ECM deposition, collagen organization, matrix remodeling, fluid shear stress, and YAP/TAZ activity. A compact ECM-associated core (ECM_Stiffness_Core; a ten-gene signature whose highest-loading members include FN1, COL1A1, COL6A1, and LOX) captured a matrix reorganization program, indicating remodeling of ECM composition and architecture rather than uniform increases in tumor stiffness, pressure, or bulk mechanical load. Matrix remodeling was associated with CAF abundance, TGFβ signaling, CD276/B7-H3, CSF1-related myeloid biology, ENTPD1/CD39, and PRDM1, whereas associations with cytotoxic immune cells were weaker. Integrin mechanosensing separated into opposing branches: ITGA5/ILK/SRC-associated features aligned with higher-risk biology and adenosine-linked immune regulation, whereas PTK2/FAK–RHOA–ROCK components showed lower-risk directions. RPPA analyses supported SRC–FAK imbalance as an adverse signaling pattern. MINER analyses further separated matrix-associated immune-suppressive regulons from canonical integrin/focal adhesion states. Conclusions: Matrix reorganization and integrin branch imbalance appear to shift ccRCC toward distinct immune-regulatory states. We propose a conceptual model that matrix architecture may act as a directional suppressive amplifier, whereas the relative balance between ITGA5/ILK/SRC-associated signaling and canonical PTK2/FAK–RHOA–ROCK mechanosensing functions as an integrin branch rheostat. This framework identifies matrix remodeling, CD276/B7-H3, CSF1-related myeloid biology, adenosine signaling, and SRC–FAK imbalance as candidate biological axes for future investigation, including their potential relevance to combination strategies beyond PD-1/PD-L1 blockade. Future experimental, spatial, and treatment response studies may further clarify the mechanistic basis of these associations and evaluate their potential therapeutic relevance. Full article

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