Background Adrenal myelolipomas are rare, benign tumors composed of adipose and hematopoietic tissue. While often asymptomatic, tumors larger than 10 cm-termed "giant"-may require surgical removal owing to the mass effect. The robotic approach to adrenalectomy offers a minimally invasive alternative to open surgery. This case is reported for its novelty, being one of the largest adrenal myelolipoma removed robotically to date. Case presentation A 36-year-old woman of South Asian ethnicity presented with mild, recurrent right flank pain for 8 months. Imaging revealed a right adrenal mass (10.5 × 10.8 × 12.2 cm), which was consistent with myelolipoma. She underwent robot-assisted laparoscopic adrenalectomy using the Da Vinci Xi platform. The tumor, which closely abutted the hepatic vein, was successfully removed without complications. Final pathology confirmed a myelolipoma measuring 18.2 × 13.5 × 5.5 cm and weighing 1030 grams—one of the largest such tumor reported to have been removed robotically. Conclusions This case highlights the feasibility and safety of robotic adrenalectomy for giant adrenal tumors in experienced hands. It sets a precedent for managing such large tumors minimally invasively and expands the scope of robotic surgery in adrenal pathology.
Background Prostate-specific membrane antigen (PSMA) PET/CT provides sensitive whole-body assessment in prostate cancer, yet the prognostic role of total tumour volume (TTV) is not fully defined in metastatic hormone-sensitive disease and needs further exploration. Methods We retrospectively reviewed patients with de novo metastatic prostate cancer undergoing baseline PSMA PET/CT at Royal North Shore Hospital between 2014-2019. TTV was quantified using a standardized Standard Uptake Value (SUV) threshold, and patients were stratified by median TTV. Associations between TTV, progression-free survival (PFS), and overall survival (OS) were assessed using Kaplan–Meier and Cox regression analyses. Results Fifty-nine patients were included in the study. Patients in the high-TTV group demonstrated reduced OS but no significant difference in PFS. Higher PSMA-derived TTV correlated with increased prostate-specific antigen (PSA) at diagnosis and higher rates of skeletal related events. Higher SUVmax was not associated with longer PFS or OS, nor was it associated with increased skeletal related events. Conclusion Baseline PSMA PET/CT-derived tumour volume is an independent prognostic biomarker in metastatic hormone-sensitive prostate cancer, associated with inferior overall survival. Incorporating TTV into existing risk models may refine patient selection for treatment intensification.
Prostate cancer is one of the major causes of cancer morbidity and mortality in men, especially at advanced stages where treatment fails. Despite the fact that the existing treatment options, such as androgen deprivation therapy, chemotherapy, radiotherapy, PARP inhibitors, and targeted agents, can successfully manage the disease progression, resistance and recurrence are frequent. Recent evidence suggests that therapy-induced senescence is dual and context dependent in prostate cancer. Although senescence at first limits tumor cell growth by halting cellular proliferation, senescent cells may nonetheless survive the treatment and cause tumor progression, immune evasion, and therapeutic resistance through the senescence-associated secretory phenotype (SASP). In addition, the senescent tumor cells can avoid the growth arrest through epigenetic reprogramming and metabolic adaptation, re-enter the cell cycle, and develop more aggressive and recurrent disease. This is a comprehensive review of the existing body of knowledge on how standard treatments induce senescence in prostate cancer cells. We cover the biological processes of senescence entry, maintenance, and escape, and the interactions between senescent tumor cells, the tumor microenvironment, and immune modulation. Also, we discuss the role of senescence in minimal residual disease, drug-tolerant persister cells, and dormant disseminated tumor cells, with a particular focus on their role in late relapse and metastasis. Lastly, the review highlights future therapeutic approaches to tackle senescent cells, such as senolytics and senomorphics, and addresses the current challenges of toxicity, biomarker discovery, and translation into clinical use. Future endeavors in the field of therapy-induced senescence can facilitate in devising treatment plans with prudent combination of senescence-based strategies to overcome therapy resistance in prostate cancer.
Background Adenoid cystic carcinoma (ACC), also referred to as basal cell carcinoma (BCC) of the prostate— a term used synonymously in the literature to describe the same clinicopathological entity— is an exceedingly rare malignant neoplasm. Initially described in the salivary glands by Billroth in 1859, ACC is characterized by cribriform, glandular, and basaloid architectural patterns. Prostatic involvement is exceptional, with only isolated case reports and small case series documented in the literature. We report a rare case highlighting the clinicopathological and immunohistochemical features essential for accurate diagnosis. Case Report A 69-year-old man presented with hematuria. Digital rectal examination and ultrasonography revealed an enlarged, hard, nodular prostate, while serum prostate-specific antigen (PSA) levels were within normal limits. Transurethral resection of the prostate (TURP) chips revealed a malignant neoplasm composed of basaloid and cribriform patterns. Immunohistochemistry demonstrated diffuse tumor cell positivity for high-molecular-weight cytokeratin (HMWCK) and BCL2, with negativity for PSA, AMACR, GATA3, CK7, synaptophysin, CD56, and chromogranin. A high Ki-67 labeling index (60–65%) supported the diagnosis of adenoid cystic (basal cell) carcinoma. Conclusion Prostatic ACC/BCC is a rare malignancy that can clinically and histologically mimic other prostatic tumors. Normal PSA levels, in conjunction with a characteristic immunophenotype, are critical for accurate diagnosis. Early recognition is essential given the tumor’s variable biological behavior and potential for aggressive progression.
Prostate-specific membrane antigen (PSMA) positron emission tomography–computed tomography (PET-CT), has become the benchmark imaging tool in the management of prostate cancer, due to its unparalleled precision in staging, restaging and assessing of treatment response. Traditional imaging modalities, such as computed tomography (CT), magnetic resonance imaging (MRI) and bone scintigraphy, suffer from subpar sensitivity, particularly in detection of small volume nodal disease and early metastatic spread. Conversely, PSMA PET-CT takes advantage of the upregulation of PSMA on prostate cancer cells to offer highly specific and sensitive molecular imaging. This review provides the contemporary overview of available literature from high-impact clinical trials, systematic reviews and meta-analyses that have described the utility of PSMA PET-CT across all stages of the prostate cancer journey. We emphasize its superior results concerning staging in the high- and intermediate-risk patients, where a better value for nodal or distant metastasis translates into individualized treatment. The review also highlights the growing importance of PSMA PET-CT imaging in biochemical recurrence, which allows early detection of recurrent disease at low prostate-specific antigen levels and individualized treatment decision making including salvage and metastasis-directed therapies. Novel applications of PSMA PET-CT in response assessment are discussed, including functional imaging biomarkers, quantitative metrics and evolving response criteria. The milestones of development and introduction of new PET tracers to support PEI for PCa are also presented in the light of radiotracers, theranostics, AI and hybrid imaging. In general, PSMA PET-CT is a leap forward in prostate cancer imaging from diagnosis to treatment based on precision medicine. Continued standardization approaches and prospective evaluation will clarify its best application in a clinical context and future oncology care pathways.
Urothelial carcinoma of the bladder (UBC) is a heterogeneous disease from the clinicopathologic and molecular standpoint and presents clinical management problems for its range in progression, frequent recurrence and complicated genetic/epigenetic architecture. Not only traditional genetic changes, but also epigenetic dysregulation (e.g., alterations of chromatin remodeling, histone modification and DNA methylation) has been increasingly recognized to play a pivotal role in the process of tumor initiation, progression, metastasis and resistance to therapy. It is a dissapointing result that mutations of the chromatin remodeler such as ARID1A, KMT2C, KMT2D, and histone modifying enzymes (EP300, CREBBP and EZH2) not only cause loss-of-nucleosome positioning in addition lead to lack of enhancer function and perturbation ofT program contributing to shaping up intratumoral heterogeneity as well as transcriptional plasticity resulting in failure in immunoevasion. These changes sculpt the tumor microenvironment and impact the response to chemotherapy, immunotherapy, and targeted therapy.Epigenetic biomarkers based on mutation profiles, chromatin accessibility and DNA methylation signatures present new non-invasive strategies that can be followed for early detection, monitoring of disease and stratification of patients usage; which are all available in urine or plasma. Therapeutically, inhibitors of EZH2, HDACs, BET proteins, DNMTs and certain chromatin remodeling factors are currently being heavily investigated in preclinical studies or clinical trials as monotherapies or rational combinations with ICIs, chemotherapy or targeted therapies.Advances in tech nologies, such as single- and spatial genomics combined with AI-facilitated multi-omics integration make it possible to realize high-resolution maps of tumor heterogeneity, enhancer d namics, and epigenetic vulnerabilities. This review aims to present the current data on UBC epigenetic modifications and their mechanistic, biomarker and therapeutic implications. By combining mechanistic understanding with translational perspectives, we outline future directions to move precision oncology forward, optimize our treatment approach and improve clinical outcomes for UBC patients.
Testicular carcinoma is the most common solid tumor in young male patients. Despite a high rate of survival, current treatments come with significant long-term toxicities, highlighting the need for more precise diagnostics and therapies. The current review focuses on the molecular pathogenesis, diagnostic development and evolving treatments of testicular germ cell tumors (TGCTs). TGCTs arise from the precursor lesion germ cell neoplasia of unclassified type or in situ (GCNIS) and consist of key genetic changes including isochromosome 12p along with changes affecting KIT/KITLG, Wnt/β-catenin, PI3K/AKT events. Recent developments in molecular and multi-omics profiling sow important differences between seminomatous and non-seminomatous subtypes and enable molecular taxonomy of the tumor as well as discovery of new targeted therapies. There is a change in the diagnostic landscape with the arrival of highly sensitive liquid biomarkers, specifically microRNA-371a-3p and circulating tumor DNA that enable precise, non-invasive monitoring and risk classification over time. Radical orchiectomy, chemotherapy and radiotherapy remain cornerstone treatments, but the field is rapidly evolving towards body- and function-sparing management. These include personalized medicine, immunotherapy, risk-stratified therapy and fertility preservation. Furthermore, we believe that the convergence of AI with molecular data improves prognostication and therapeutic decision making, ultimately guiding the field to less toxic and more effective patient-quality care.
Eosinophilic solid and cystic renal cell carcinoma (ESC-RCC) is a recently characterized renal neoplasm, typically indolent, with rare instances of metastasis. We report an 85-year-old male patient presenting with left knee pain. Magnetic resonance imaging (MRI) revealed an osteolytic lesion in the left proximal tibia. Subsequent imaging identified a primary renal mass with renal vein thrombosis. Histology showed a highly cellular infiltrative neoplasm with eosinophilic to clear cells arranged in solid sheets and papillaroid pattern. Immunohistochemistry showed diffuse positivity for PAX8, AMACR, vimentin and focal positivity for CD10 and KRT20 favouring metastatic ESC-RCC. This case underscores the potential for ESC-RCC to exhibit aggressive behavior with distant metastasis, highlighting the need for awareness of its variable clinical course and strong suspicion in evaluating KRT7 negative and KRT20 positive metastatic carcinomas.
Adrenocortical carcinoma (ACC) is a rare and highly aggressive endocrine cancer type, posing significant clinical challenges due to its diverse molecular features and poor treatment outcomes. At the molecular level, abnormalities in pathways, such as IGF2 signaling, Wnt/β-catenin activation, cell-cycle regulation, DNA damage repair, chromatin remodeling, and steroidogenesis have been implicated in ACC biology. The complex tumor microenvironment, marked by immune exclusion, angiogenic activity, and cortisol-driven immunosuppression, contributes to tumor progression and therapy resistance. A growing shift toward more precise and mechanism-based therapeutic strategies has led to the advent of several targeted approaches, such as IGF-1R and mTOR inhibition, VEGFR- and multi-kinase-directed therapies, and Wnt and cell-cycle modulators. These approaches have shown promising preclinical anti-tumor activity, though clinical benefit remains variable. Immunotherapy has also emerged as an important frontier in the treatment of ACC, with PD-1/PD-L1 inhibitors, dual checkpoint blockade, combination treatments with VEGFR tyrosine kinase inhibitor and immune checkpoint inhibitor, and glucocorticoid receptor modulation showing encouraging results, especially in patients with microsatellite instability-high tumors. Furthermore, next-generation therapeutic platforms, including radiopharmaceuticals, antibody-drug conjugates, neoantigen-based vaccines, engineered cellular therapies, nanotechnology-based delivery systems, and AI-driven biomarker and drug discovery, are novel avenues being explored in the field ACCs. Collectively, this review explores these insights contributing to the evolving precision therapy paradigm that has the potential to reshape the therapeutic management of ACC and provide more individualized options for patients in the future.
Background Urothelial carcinoma of the urinary bladder exhibits heterogeneous biological behavior, even among tumors of similar histological grade and stage. Estrogen receptor beta (ER-β), the predominant estrogen receptor subtype in urothelial tissue, has been implicated in bladder carcinogenesis and tumor progression. Objectives To evaluate the immunohistochemical expression of ER-β in urothelial carcinoma of the urinary bladder and to analyze its association with histological grade and muscle invasion. Materials and Methods This cross-sectional observational study included 100 cases of urothelial carcinoma diagnosed on transurethral resection or cystectomy specimens. Tumors were classified as low-grade or high-grade according to WHO criteria. Immunohistochemical staining for ER-β was performed, and nuclear expression was assessed semi-quantitatively using a three-tier scoring system. Statistical analysis was performed using the chi-square test. Results ER-β expression was observed in all cases. Moderate to strong ER-β expression (scores 2 and 3) was significantly more frequent in high-grade tumors compared to low-grade tumors (p < 0.001). A statistically significant association was also noted between higher ER-β expression and muscle-invasive disease (p = 0.027). Conclusion ER-β is consistently expressed in urothelial carcinoma, with higher expression significantly associated with adverse histopathological features such as high tumor grade and muscle invasion. These findings support the potential role of ER-β as a prognostic biomarker and a possible therapeutic target in urothelial carcinoma.
High Mobility Group Box 1 (HMGB1) is non-histone chromatin protein that plays important roles in maintaining nuclear architecture, transcriptional modulation, DNA replication, chromatin restructuring and DNA damage repair. In addition to its classical nuclear roles, HMGB1 predominantly functions as an extracellular alarmin and damage-associated molecular pattern (DAMP) signal that stimulates various receptors such as Toll-like receptor's (TLRs) or Receptor for Advanced Glycation End Products (RAGE), influencing inflammation and immune system regulations. HMGB1 function is strictly regulated, not only by posttranslational modifications and subcellular localization, but also critically by its redox status that is regulated by three conserved cysteine residues (C23, C45, C106). Its chemotactic (fully reduced), cytokine inducing (disulfide) or immunologically inert function (fully oxidized) is determined by these redox forms. HMGB1 is upregulated in Clear Cell Renal Cell Carcinoma (ccRCC), the gold standard for RCC diagnosis, where it is often found overexpressed and mislocalized to cytoplasm as wells as being posttranslationally modified, enhancing protumorigenic microenvironment. Hyperactivated HMGB1 drives chronic inflammation, autophagy dependent tumor survival, immune suppression and angiogenesis and genomic instability that links nuclear malfunction to the extracellular cascade in ccRCC progression. Such an orchestration involving redox-mediated HMGB1 signaling is both pro-tumoural inflammatory and anti-genomic maintenance. Therapeutically, the blockade of HMGB1's redox status, its interaction with receptors or autophagy-associated function can be promising strategies to control growth and sensitize treatment. Additionally, the expression of HMGB1 forms, their cellular localization, and redox state in circulation are potential prognostic and predictive biomarkers. Here we provide an in-depth discussion on the molecular mechanisms related to HMGB1 deregulation in promoting the pathogenesis of ccRCC, and shed light on potential translational applications for clinical intervention.
Prostate cancer is a major health problem in the world, and it has been complicated by the fact that the illness is quite heterogeneous. In the past, the use of PSA testing and histopathological grading has been constrained by failure to reliably distinguish between indolent and aggressive cancer. In this review, the concept of a fundamental change in the field of prostate cancer treatment, facilitated by the development of molecular diagnostics, is discussed. We discuss how genomic classifiers, epigenetic assays, and commercially available tests of biomarkers are being integrated to make risk stratification much more precise and tailored treatment decisions. Also, the stage of imaging, especially PSMA-targeted PET, breakthrough is transforming the accuracy of staging. Dynamic monitoring of tumor evolution has now been made possible by the introduction of liquid biopses, which can be used to study tumor-derived signals in the blood in a non-invasive manner. It is these diagnostic advances that are directly leading to a new generation of therapies that are targeted such as PSMA-directed radioligand therapy and drugs that target molecular weaknesses in cancer cells. Although this is a promising development, to achieve the full potential of precision medicine, the various obstacles, including tumor evolution, and clinically-implementation obstacles must be overcome. It is important to note that more efforts should be put to perfect these tools and strategies in the long run to enhance the results and life of men who have this disease.
Prostate cancer is a metabolically distinct malignancy as it exhibits strong flexibility in how it uses energy and perform physiological processes. In contrast to many solid tumors which mostly depend on aerobic glycolysis, the primary prostate cancer cells still depend mainly on oxidative phosphorylation and tricarboxylic acid (TCA) cycle for energy supply. This unique metabolic pattern is mainly controlled by androgen receptor signaling and also affected by mitochondrial functions and zinc level inside the cells. When the disease goes into advanced stage, especially castration-resistant prostate cancer (CRPC), the tumor cells change their energy system toward glycolytic and lipogenic ways to support hyperactive cell cycle, therapy resistance, and metastasis. This review gives a detailed discussion about metabolic reprogramming in prostate cancer with focus on glycolysis, mitochondrial dysfunction, and dysregulated lipid and cholesterol metabolism. Key enzymes, transporters and transcription factors, such as GLUT1, HK2, PFK1, PKM2, LDHA, PDK, FABP5, ACLY, ACAC, FASN, SREBPs and LXRs are discussed as important players of tumor bioenergetics , and as possible drug targets. Especially lipid metabolism has shown strong relation with CRPC aggressiveness, which is promoted by androgen receptor-controlled increase of lipogenic enzymes and fatty acid transport process. Interaction between metabolic pathways and oncogenic signaling like PI3K/AKT/mTOR makes the situation more complex. The review also covers new therapeutic strategies which make use of these metabolic vulnerabilities, including small molecule inhibitors, natural substances, and combination treatments. Better understanding of metabolic reprogramming of prostate cancer at different disease stages can help in creating more specific therapies to overcome resistance and improve clinical outcomes.
Bladder cancer is a significant global health challenge. Despite advances in surgery and platinum-based chemotherapy over the decades, limited improvements in clinical outcomes have been observed. However, recent years have witnessed the development of immune checkpoint inhibitors (ICIs) and antibody-drug conjugates (ADCs) that has transformed the therapeutic landscape of bladder cancer across different disease stages. ICIs block inhibitory pathways including PD-1/PD-L1 and CTLA-4 and reawake antitumor immunity, whereas ADCs, the combination of tumor-selective antibodies with potent cytotoxic payloads, ensure targeted cancer cell death with less systemic toxicity. Both therapies have exhibited clinical benefit in bladder cancer individually and in combination. Clinical trials including NIAGARA, CheckMate-274, and EV-302, have defined new perioperative and first-line standards based on ICIs and ADCs. Ongoing advancements in HER2-, Trop-2-, and Nectin-4-directed ADCs, bispecific and small-molecule conjugates, and combination with ICIs are revolutionizing the therapeutic options for bladder cancer. Of note, the combination of an ADC, enfortumab vedotin, with ICI, pembrolizumab, has improved survival in advanced disease scenarios in bladder cancer. Resistance against ICIs and ADCs remains a significant challenge, but identifying predictive biomarkers, integrating molecular profiling with these therapies, and developing effective combination strategies hold strong potential to achieve durable, precise, and personalized treatment outcomes for bladder cancer.
Background Primary renal leiomyosarcoma (LMS) is an exceptionally rare malignant mesenchymal tumor, constituting <1.5% of all primary renal malignancies. Diagnosis is difficult because clinical and radiologic features overlap with other renal neoplasms. Case Presentation We describe a 37-year-old woman, notably younger than the typical age reported for renal LMS, who presented with abnormal uterine bleeding and incomplete abortion. During gynaecologic imaging, an incidental exophytic right-renal mass was detected. CECT and CT angiography revealed a heterogeneously enhancing lesion with necrosis abutting adjacent structures. The patient underwent laparoscopic radical nephrectomy. Histopathological examination showed fascicles of spindle cells with pleomorphism, atypical mitoses, and necrosis involving <50% of tumor area. Immunohistochemistry confirmed smooth muscle differentiation with positivity for vimentin, desmin, and SMA, while negative for cytokeratin, S100, and HMB-45. A final diagnosis of well-differentiated primary renal leiomyosarcoma (FNCLCC grade 1, stage pT3aNxMx) was rendered. The postoperative course was uneventful, and the patient remains well at 3-month follow-up. Conclusion This case is novel for its incidental detection during gynaecologic evaluation for incomplete abortion and for occurring in a young female patient (37 years), whereas most reported renal LMS present later in life and at higher grade. These features underscore the importance of considering LMS in atypical contexts and highlight the need for awareness among both urologists and gynaecologists.
Primary bladder adenocarcinoma (PBA) is a rare malignancy comprising of only 0.5–2% of all bladder cancers and typically presents with nonspecific urinary symptoms. Cystic presentation is extremely uncommon and can mimic other pelvic pathologies. We report a very rare case of PBA in a 40-year-old female initially diagnosed as ovarian torsion based on clinical features and ultrasound findings. Intraoperatively, a cystic mass was seen on bladder dome which on frozen suggested malignancy leading to diagnosis of urachal adenocarcinoma. But in resected specimen, histopathology along with immunohistochemistry confirmed the diagnosis of enteric-type PBA after ruling out its differentials like urachal, urothelial and metastatic adenocarcinoma. To the best of our knowledge, this is the first reported case of cystic PBA. This case highlights the diagnostic challenges and the need for a broad differential in pelvic mass evaluation.
Renal cancer (RC) ranks tenth among the most frequently diagnosed cancers and affects both men and women worldwide. This disease is a significant global health issue, highlighting the need for accurate and rapid diagnostic tools to guide treatment. Conventional pathological methods have drawbacks, such as extended evaluation procedures and inter-observer inconsistency. Recent developments in artificial intelligence (AI) have enabled the progress of AI-powered computer-assisted diagnostic and predictive systems for various diseases, including cancer. A comprehensive literature review examined the latest advancements in AI and RC technologies. Advanced image analysis methods enable AI systems to measure molecular and cellular markers, thereby improving the precision and reproducibility of RC detection. This narrative review highlights the basic ideas and comprehensively summarizes modern AI methods for RC. Early clinical outcome prediction, renal carcinoma subtyping, grading, staging, and disease identification are only areas in which their potential has been demonstrated. Before applying this in daily practice, healthcare practitioners must understand the fundamentals and interact across different fields to standardize datasets, establish relevant outcomes, and merge interpretations.
Objective Previous data suggest that Angiotensin system inhibitors (ASIs) may exert antitumor effects; however, the findings remain controversial. Therefore, the present study was conducted to evaluate the association between concomitant use of ASIs and survival outcomes in patients with renal cell carcinoma (RCC). Methods We conducted a comprehensive search of electronic databases, including PubMed and Web of Science, to identify relevant studies according to the predefined inclusion and exclusion criteria. The pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using either random-effects or fixed-effects models, as appropriate. Results Favourable overall survival (OS) was observed in patients using ASIs compared with non-users (hazard ratio [HR] = 0.68, 95% CI: 0.57–0.81; p = 0.000). In the subgroup analysis, OS benefits were evident across treatment agents, the time window of ASI use, and in patients with metastatic renal cell carcinoma (mRCC). Moreover, progression-free survival (PFS) and disease-specific survival (DSS) benefits were observed in ASI users compared to non-users (HR = 0.74, 95% CI: 0.62–0.87; p = 0.000). Additionally, consistent DSS and PFS advantages were noted across treatment agents, mRCC, and the time window for ASI use. Conclusion Our findings indicate that concomitant use of ASIs is significantly associated with improved survival outcomes in patients with RCC. Further high-quality studies are required to validate these conclusions.
Primary mucinous adenocarcinoma (PMA) of the urinary bladder is a rare and aggressive neoplasm, accounting for 0.5-2% of bladder malignancies. We report a case of a 52-year-old male presenting with urinary obstructive symptoms and hematuria. Imaging revealed a bladder mass, and histopathology confirmed muscle-invasive mucinous adenocarcinoma with characteristic mucin pools and signet ring cells. Immunohistochemistry ruled out secondary metastasis, supporting a primary bladder origin, following which the patient underwent radical cystectomy. This case highlights the importance of integrated clinicopathological assessment for accurate diagnosis and management of PMA, contributing valuable insights to this uncommon entity.
Kidney cancer, particularly clear cell renal cell carcinoma (ccRCC), has emerged as a paradigm for cancer metabolic reprogramming, exhibiting distinctive alterations that drive tumor progression and therapeutic resistance. This comprehensive review synthesizes current knowledge of the molecular mechanisms underlying metabolic dysregulation in kidney cancer, with emphasis on the central role of VHL/HIF pathway activation and its downstream consequences on glycolysis, lipid metabolism, and glutamine utilization. We systematically analyze how pseudohypoxia-driven metabolic rewiring not only supports tumor bioenergetics and biosynthesis but also shapes an immunosuppressive microenvironment through metabolite-mediated crosstalk with stromal and immune cells. The review highlights groundbreaking therapeutic advances, including FDA-approved HIF-2α inhibitors and emerging agents targeting glycolytic enzymes, glutaminase, and lipid metabolism, while addressing the challenges of metabolic plasticity and acquired resistance. Special attention is given to innovative combination strategies that pair metabolic modulators with immunotherapy or tyrosine kinase inhibitors, supported by preclinical rationale and clinical trial data. We further discuss cutting-edge technologies transforming the field - from hyperpolarized MRI for real-time metabolic imaging to AI-driven analysis of multi-omics datasets for patient stratification. By integrating fundamental science with translational applications, this review provides a framework for understanding kidney cancer as a metabolic disease and outlines future directions for targeted therapies, biomarker development, and personalized treatment approaches. The synthesis of these insights offers both a conceptual foundation and practical guidance for researchers and clinicians working to exploit metabolic vulnerabilities in kidney cancer.
