Search Results (2,024)

Background: Robot-assisted partial nephrectomy (RAPN) has become the preferred surgical approach for localized renal tumours, yet the optimal surgical technique remains uncertain. Ongoing refinements aim to reduce morbidity while maximizing renal function preservation. In this study, we compared perioperative outcomes, postoperative complications, and early renal function between the no-touch adaptive RAPN technique, designed to minimize vascular and parenchymal trauma, and the conventional approach. Methods: We retrospectively analyzed 387 consecutive patients undergoing RAPN for localized renal tumours between June 2017 and February 2026 at a single tertiary referral centre. Patients were treated with either the no-touch adaptive (n = 178) or conventional (n = 209) technique. The no-touch approach consisted of sutureless off-clamp simple tumour enucleation with incremental haemostasis and on-demand conversion to arterial clamping, tumour enucleoresection, or renorrhaphy when required. The conventional technique consisted of an on-clamp minimal enucleoresection with double-layer renorrhaphy. Completion rate of a fully no-touch procedure was assessed in the study group, and perioperative outcomes, 90-day complications, and renal function at 3 months were compared between the groups. Exploratory multivariable logistic regression identified predictors of postoperative complications. Absolute and relative changes in estimated glomerular filtration rate (eGFR) from baseline were analyzed, and a linear regression model adjusted for baseline eGFR was used to compare postoperative renal function between the groups. Results: Among the 175 evaluable patients after excluding three immediate conversions to radical nephrectomy before tumour excision, a fully no-touch procedure was completed in 153 (87.4%). Compared with conventional RAPN, the no-touch group had a significantly shorter hospital stay (3 vs. 5 days, p < 0.01), lower 90-day readmission rate (0% vs. 4.3%, p = 0.01), fewer overall complications (16.3% vs. 40.7%, p < 0.01), and fewer major complications (3.9% vs. 11%, p = 0.02), with no cases of delayed vascular bleeding. Low tumour complexity and the no-touch technique independently predicted a lower risk of postoperative complications. The median decline in eGFR from baseline to 3 months was significantly smaller in the no-touch group, which also showed a lower rate of clinically meaningful renal function deterioration (eGFR decline ≥ 30%; 1.1% vs. 5.7%, p = 0.03). After adjustment for baseline eGFR, the no-touch adaptive technique was associated with a 5.4 mL/min/1.73 m² higher 3-month eGFR than the conventional technique (95% CI 3.6–7.2; p < 0.001). Conclusions: Within the limitations of this retrospective comparative study, the no-touch adaptive technique for RAPN was associated with lower perioperative morbidity and better preservation of early renal function than the conventional approach. These findings support further prospective multicentre studies to determine the reproducibility, durability, and clinical relevance of this surgical strategy. Full article

Background: Balkan nephropathy (BEN), caused by chronic dietary exposure to aristolochic acid (AA), is a tubulointerstitial kidney disease strongly associated with upper-tract urothelial carcinoma (UTUC). Patient and graft survival, the cumulative incidence and timing of post-transplant UTUC, and the burden of non-urothelial malignancy after kidney transplantation remain poorly defined. Methods: We retrospectively analyzed all patients with BEN as the primary cause of end-stage kidney disease transplanted at University Hospital Center Zagreb between October 1973 and December 2023. Outcomes included patient and graft survival, the incidence and timing of post-transplant UTUC, and burden of non-urothelial malignancies. Results: Of 2282 kidney transplants performed in the study period, 44 (2%) were in patients with BEN. The median age at transplantation was 56 years, and the median dialysis vintage was 3.7 years. After 10 years (median) of follow up, among 34 patients with adequate follow-up, 16 (47%) developed a de novo malignancy: eight (24%) UTUC, one renal cell carcinoma, four other solid tumors, and three hematological. UTUC was diagnosed between 6 months and 15 years post-transplant (median 7 years); five of eight patients died within one year of diagnosis. Five- and ten-year patient survival rates were 82% and 54.5%. Conclusions: Kidney transplantation in patients with BEN carries a lifelong cancer risk dominated by UTUC. Prophylactic bilateral nephroureterectomy should be the default management strategy when feasible, with lifelong surveillance extending beyond the urothelium. 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 and Objectives: During the 2016–2022 period, tyrosine kinase inhibitor (TKI) monotherapy was the standard first-line option at our center before combination protocols became available. This study evaluates patients experiencing initial TKI failure who subsequently received second- or later-line nivolumab. Because clinical practice lacks low-cost, accessible tools to prognosticate outcomes in this setting, we evaluated whether baseline psoas muscle index (PMI), early on-treatment C-reactive protein (CRP) kinetics, and a specific panel of blood-derived inflammatory/nutritional ratios offer reliable prognostic value. Materials and methods: We retrospectively reviewed data from 49 consecutive mRCC patients who progressed on a TKI and received second- or later-line nivolumab monotherapy. Primary endpoints were overall survival (OS; N = 49) and time-to-treatment failure (TTF; N = 48). We utilized Kaplan–Meier and Cox regression models for analysis. Benjamini–Hochberg false discovery rate (FDR) correction (q < 0.05) controlled false positive inflation across two separate testing frameworks: seven log-rank assessments for TTF and the core Cox models. Adjusted models accounted for clinical covariates including International Metastatic RCC Database Consortium (IMDC) risk category, Eastern Cooperative Oncology Group performance status (ECOG PS), and de novo metastatic presentation. We calculated the intraclass correlation coefficient (ICC) to evaluate measurement reproducibility. Results: Median follow-up reached 48.4 months (reverse Kaplan–Meier; maximum: 87.8 months), with a cohort-wide median OS of 13.9 months (IQR: 5.8–36.2). A low baseline C-reactive protein-to-albumin ratio (CAR) mapped to a distinct survival benefit, showing a median OS of 32.6 months versus 5.8 months in the high-CAR group (log-rank p < 0.001; BH q = 0.003). In adjusted multivariable Cox hazards modeling, both CAR (HR: 1.029; p = 0.002) and the prognostic nutritional index (PNI; HR: 0.893; p < 0.001) maintained independent prognostic significance. When evaluating the 43 patients with complete 3-month CRP records, we found a significantly higher objective response rate (ORR) in those at or below the cohort-median ratio threshold of 1.16 compared to patients above it (54.5% vs. 23.8%; p = 0.039). The overall ITT population registered an ORR of 36.7% (18/49). Conclusions: Low pretreatment CAR and elevated PNI identify mRCC patients showing improved survival profiles in this post-TKI nivolumab subgroup. Additionally, an elevated 3-month CRP ratio correlates with compromised objective response rates and a trend toward shorter TTF, though the TTF endpoint did not clear strict FDR parameters (BH q = 0.098). These retrospective, single-center data serve strictly for signal generation and require independent prospective multi-institutional confirmation before translating to oncology practice. Full article

Copper is essential for mitochondrial respiration, antioxidant defense, extracellular matrix maturation, and cellular signaling, yet disturbances in its abundance or intracellular distribution can damage the kidney through mechanistically distinct pathways. Cuproptosis is a specific copper-dependent form of regulated cell death in which copper binds lipoylated mitochondrial proteins, promotes aggregation of tricarboxylic acid cycle components, destabilizes iron–sulfur cluster proteins, and elicits FDX1- and protein lipoylation-dependent proteotoxic stress. This mechanism should be distinguished from broader copper-associated injury, including redox imbalance, glutathione depletion, respiratory-chain inhibition, senescence, apoptosis, and lysyl oxidase-mediated matrix remodeling. This narrative review examines how renal copper uptake, trafficking, and compartmentalization interact with cell-specific metabolism to shape copper-related cell fates across acute kidney injury, nephrotoxicity, renal ischemia–reperfusion injury, crystal- and lipid-related tubular injury, diabetic kidney disease, podocyte injury, chronic kidney disease and renal fibrosis, end-stage renal disease, renal cell carcinoma, and hereditary copper disorders. Mechanistic evidence is strongest in selected acute tubular, crystal-injury, and renal cancer models, in which transporter manipulation, DLAT oligomerization, iron–sulfur perturbation, or functional rescue has been demonstrated. In chronic kidney disease and fibrosis, copper-DLAT interactions, complex IV inhibition, COMMD1-SOD1 dysfunction, and ATP7A-FBLN4-LOX signaling establish pathogenic copper dependence but do not yet demonstrate a complete canonical cuproptosis pathway. By integrating disease-specific evidence with the molecular determinants of copper handling and protein lipoylation, this review identifies current therapeutic opportunities, candidate biomarkers, and key research priorities while preserving the distinction between cuproptosis and other forms of copper-associated kidney injury. Full article

Hereditary kidney cancer syndromes predispose patients to multifocal, bilateral and/or recurrent renal tumors, requiring repeated interventions over a lifetime. Despite nephron-sparing surgery being the preferred management strategy, some patients ultimately require completion nephrectomy—radical nephrectomy following prior ipsilateral partial nephrectomy—when tumor burden, declining renal function, surgical complications, or pre-transplant indications necessitate definitive kidney removal. Data on outcomes in this population remain limited. We evaluated a prospectively maintained cohort of 58 patients who underwent completion nephrectomy at the National Institutes of Health between 2000 and 2024, following at least one prior ipsilateral partial nephrectomy. Perioperative complication rates and renal functional change were the primary outcomes of interest. Von Hippel–Lindau disease was the most common hereditary diagnosis (62.1%). Open surgery was performed in 56.9% of cases. Overall complications occurred in 43.1% of patients, with 24.1% experiencing a Clavien–Dindo grade ≥ 3 event; perioperative mortality was 6.9%. The median preoperative estimated glomerular filtration rate was 72 mL/min/1.73 m², declining to 50 mL/min/1.73 m² at the first postoperative clinic visit. Completion nephrectomy in hereditary kidney cancer syndrome patients is associated with substantial perioperative morbidity, mortality, and expected renal functional decline. These findings inform patient counseling and surgical decision-making in this high-risk population. 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

Immune checkpoint inhibitor-related pneumonitis (CIP) is an uncommon but clinically relevant toxicity in renal cell carcinoma (RCC), where immune checkpoint inhibitors are frequently used either as dual immunotherapy or in combination with VEGF-targeted tyrosine kinase inhibitors. In RCC, CIP poses specific diagnostic challenges because respiratory symptoms and computed tomography findings may overlap with pulmonary metastases, infections, thromboembolic events, heart failure, and TKI-related lung toxicity. This review summarizes the incidence of CIP across pivotal RCC trials and real-world cohorts, compares its epidemiology with non-small cell lung cancer, and discusses clinical presentation, radiological patterns, differential diagnosis, and current management strategies. Particular attention is given to RCC-specific mechanisms, including immune-mediated alveolar injury, T cell activation, cytokine dysregulation, macrophage activation, GSDME-mediated pyroptosis, and the potential contribution of VEGF pathway inhibition to pulmonary inflammation. We also review risk factors, steroid-refractory disease, second-line immunosuppression, and the unresolved issue of ICI rechallenge after pneumonitis. A better understanding of these mechanisms and clinical features may improve early recognition, guide multidisciplinary management, and support safer use of immunotherapy-based combinations in patients with RCC. 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

Bone metastasis is often treated clinically as a late complication of advanced cancer, yet accumulating evidence indicates that it is also a spatial evolutionary process shaped by clonal selection, niche adaptation, dormancy, and reseeding. This review examines BoM through a phylogeographic framework that links tumor ancestry with anatomical location and time. We discuss how heterogeneous primary tumors generate bone-tropic subclones, how circulating tumor cells pass through dissemination bottlenecks, and how disseminated tumor cells enter perivascular and endosteal niches that either maintain dormancy or support early micrometastatic outgrowth. We then compare clonal architectures across breast, prostate, lung, and renal cell carcinomas, emphasizing both lineage-specific programs and convergent bone-adaptive states, including osteomimicry, immune evasion, metabolic plasticity, and epigenetic remodeling. Methodological platforms such as multiregion sequencing, single-cell and spatial transcriptomics, lineage tracing, and liquid biopsy are evaluated with attention to the technical limitations imposed by mineralized tissue. Finally, we consider how bone lesions may function as reservoirs for secondary dissemination and how evolutionary thinking could improve biomarker development, dormancy prediction, trial design, and therapy selection. Viewing BoM as an evolving ecosystem may help shift the field from reactive skeletal management toward earlier, biology-informed intervention. Full article

Background: Pazopanib, cabozantinib, sorafenib, axitinib, tivozanib, and sunitinib are widely used tyrosine kinase inhibitors (TKIs) targeting the vascular endothelial growth factor receptor signaling pathway. Considerable interindividual pharmacokinetic variability, together with established exposure–toxicity relationships, underlines the need for reliable analytical methods for therapeutic drug monitoring (TDM). The aim of this study was to develop and validate an LC–MS/MS method for the simultaneous determination of these six TKIs and the two metabolites, sorafenib N-oxide and desethyl-sunitinib, in human plasma and to investigate their stability under relevant preanalytical conditions. Methods: Plasma samples were prepared by protein precipitation and analyzed using LC–MS/MS with positive electrospray ionization and multiple reaction monitoring. Validation included assessments of linearity, accuracy, precision, lower limit of quantification, dilution integrity, carry-over, and stability under different storage conditions. As proof of concept, the method was applied to plasma samples from patients receiving TKI treatment. Results: All analytes demonstrated linear responses across the validated calibration ranges. Validation parameters met predefined acceptance criteria for all analytes, except for sorafenib N-oxide, which exhibited CV% values slightly above the acceptance limit (15%). All compounds remained stable during storage at −80 °C for at least five years. Furthermore, all analytes were stable at room temperature for 24 h, except sorafenib N-oxide, which showed instability under these conditions. Analysis of patient samples confirmed the suitability of the method for clinical application. Conclusions: We established and validated a fast, sensitive, and accurate LC–MS/MS method enabling simultaneous quantification of six TKIs and two metabolites in human plasma. The analytical method was successfully applied to plasma samples from patients in treatment with the six TKIs, demonstrating proof of concept for its application in TDM. 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

Background/Objectives: To date there is a lack of an integrative review literature on redox homeostasis, oxidative stress and the influence on metabolic pathways and plasticity in uveal melanoma (UM), since most literature findings are from cutaneous melanoma (CM), a genetically and behaviorally distinct cancer. Furthermore, UM metabolic pathway comparison to other cancers could provide more insight into metastatic UM, a difficult-to-treat malignancy. Methods: A wide-ranging multi-step literature search of PubMed and Web of Science for redox balance, oxidative stress, antioxidants and metabolic plasticity in UM, with expanded search terms for connections with other cancers. Results: UM cells maintain redox homeostasis via several redox loops: glutathione, thioredoxin, peroxiredoxins, peroxisomal catalase and the mitochondrial antioxidative network. NADPH plays a key role in regenerating UM antioxidative capabilities. Key redox signaling pathways are the subject of ongoing research in UM: NRF2 signaling, AMPK, mTOR, MAPK, FoxO. These pathways are less studied versus CM and present behavior differences in UM. PON2, studied in CM, represents a literature gap in UM. Inside the tumoral microenvironment, UM presents high metabolic plasticity and easy switching from glycolysis to oxidative phosphorylation (OXPHOS). Thus, UM eschews the classic Warburg effect loop and instead presents high oxidative phosphorylation (OXPHOS) gene expression, which generates additional lactate, which in turn produces cascade reprogramming in the metabolic pathways and lactate metabolism particularities associated in experimental studies with immune-escape phenomena. Uveal melanoma’s OXPHOS capabilities confer survival advantages and subdivide tumoral populations into OXPHOS-high and OXPHOS-low variants. Glycolysis/OXPHOS metabolic plasticity is an ongoing research field in other cancers with common and different elements vs. UM: cutaneous melanoma, small cell lung carcinoma, pancreatic cancer, breast cancer, acute myeloid leukemia, prostate cancer, renal cell carcinoma and glioblastoma. Uveal melanoma cells are susceptible to deleterious effects of prooxidants, a metabolic vulnerability which helps to create genetic pleomorphism, selecting higher proliferation and dissemination variants. Conclusions: Uveal melanoma is an oncogenic mutation and mitochondrial metabolism-driven malignancy, with metabolic connections to other malignancies. Emerging understanding of redox homeostasis, redox pathway signaling, mitochondrial oxidative and oncogenic metabolism could lead to better understanding of therapeutic response and new therapeutic targets. This review novelly integrates the general and CM redox literature with the UM literature, painting a complex redox signaling and metabolic plasticity picture of UM. Full article