Review Article | Open Access
Metabolic Supremacy Fuels Tumor Aggressiveness in Renal Cancer
Reham Gholam1, Muhammad Khalilzad21Department of Pharmacognosy, Daras Gah Mili Building, Islamic Azad University, ZIP area 11, Azarshahr Street, Karimkhan-e-Zand Avenue, Tehran 1477893780, Iran.
2Department of Basic Medical Science, Block 15, Islamic Azad University, ZIP area 11, Azarshahr Street, Karimkhan-e-Zand Avenue, Tehran 1477893780, Iran.
Correspondence: Muhammad Khalilzad (Department of Basic Medical Science, Block 15, Islamic Azad University, ZIP area 11, Azarshahr Street, Karimkhan-e-Zand Avenue, Tehran 1477893780, Iran; Email: Khalilzadah888@yahoo.com).
Annals of Urologic Oncology 2025, 8: 5. https://doi.org/10.32948/auo.2025.03.01
Received: 08 Jan 2025 | Accepted: 25 Feb 2025 | Published online: 02 Mar 2025
Key words renal cancer, hypoxia, Warburg effect, lipid metabolism, amino acid metabolism
First identified several decades ago, metabolic reprogramming has emerged as a primary focal point for new cancer treatments. It enables tumors to adapt biochemical pathways to satisfy escalated energy requirements and biosynthesis, thus presenting novel targets for intervention [10]. Early studies characterized the heightened glycolysis in cancer cells, known as the “Warburg effect”, as a reflection of inefficient energy generation [11]. However, modern evidence implicates oncogenic mutations in driving widespread metabolic alterations, influencing glucose uptake, lipid synthesis, and mitochondrial oxidative phosphorylation to advance tumorigenesis [12]. Even when oxygen is plentiful, cancer cells deplete local nutrient stores by favoring glycolysis over oxidative phosphorylation and establish an immunosuppressive environment that impairs T-cell function, thereby promoting tumor progression [13]. These metabolic abnormalities are particularly pronounced in ccRCC, with genetic disruptions triggering shifts in glucose metabolism, increased glutamine reliance, and mitochondrial dysfunction [14, 15]. The Warburg effect, exemplified by the bias toward rapid ATP generation while also producing building blocks vital for cellular proliferation, is a hallmark of ccRCC [16]. Hence, recognizing the relationship between metabolic dysregulation and ccRCC pathogenesis is essential for designing more effective treatments. Here, we explore the molecular mechanisms behind metabolic supremacy in ccRCC, focusing on dysfunctional hypoxic signaling, aberrant glucose metabolism, Warburg effect, dysregulated amino acid metabolism and elevated lipid metabolism as key culprits behind tumor aggressiveness. We also discuss the pharmacological interventions targeting these pathways, including agents that inhibit glycolysis, glutaminolysis, and fatty acid oxidation. By mapping the metabolic framework of ccRCC, this review aims to guide future research and therapeutic innovations intended to overcome tumor aggressive in renal cancer, critical to limit tumor burden and enhance patient survival in this malignancy.

Glycolysis involves breaking glucose down into pyruvate [42]. Pyruvate enters the TCA cycle under aerobic conditions, supporting ATP generation along with the production of reduced nicotinamide adenine dinucleotide (NADH) and reduced flavin adenine dinucleotide (FADH2) [43]. Under anaerobic conditions, pyruvate is converted into lactate by fermentation, yielding ATP [44]. In ccRCC, another essential metabolic pathway is the pentose phosphate pathway, which generates glucose for lipid metabolism and nucleic acid synthesis by producing reduced nicotinamide adenine dinucleotide phosphate (NADPH) and ribose 5-phosphate [45]. The pentose phosphate pathway is significantly heightened in ccRCC, producing abundant NADPH necessary for preserving redox balance and safeguarding cancer cells from reactive oxygen species (ROS) damage [46]. This metabolic adjustment helps tumor cells mitigate oxidative stress and limit ROS-induced harm [47]. Additionally, the pentose phosphate pathway furnishes the five-carbon sugars required for nucleotide production, meeting the heightened demands of rapidly proliferating tumor cells [48]. Significant modifications also occur within the TCA cycle in ccRCC, contributing to its distinctive metabolic profile. Enzymes essential for refilling metabolic intermediates from other pathways are frequently reduced [49]. Of note, citrate and cis-aconitate are found in higher concentrations in ccRCC’s TCA cycle, whereas malate and fumarate are markedly decreased [15]. The drop in fumarate and malate is largely tied to the inhibition of succinate dehydrogenase (SDH), a mechanism that continuously diminishes fumarate and, by extension, malate [49]. This observation contradicts the typical notion of tumor tissues maintaining abundant fumarate. Overall, the abnormal regulation of glucose metabolism, primarily steered by HIF-1α and HIF-2α, plays a pivotal role in ccRCC aggressiveness. Collectively, overexpression of glycolytic enzymes, and alterations in the TCA cycle and pentose phosphate pathway grant ccRCC a metabolic advantage that propels its progression (Figure 2).

Tryptophan also critically modulates T cell-mediated immune responses to tumors. However, its excessive oxidation through the kynurenine pathway triggers T cell dysfunction and allows tumor cells to evade immune detection [66]. Metabolites in the kynurenine pathway actively suppress T cell activation, exacerbating immune escape. Within tumor-draining lymph nodes, elevated indoleamine 2,3-dioxygenase (IDO) activity creates an immunosuppressive milieu by prompting dendritic cells to inhibit T cells, thereby interfering with antigen recognition and immune function [67]. In ccRCC, immune checkpoint dysregulation is associated with increased IDO expression, which depletes tryptophan and activates the kynurenine pathway, ultimately supporting tumor survival by countering interferon-alpha (IFN-α) therapy and fostering immune suppression (Figure 2) [68, 69]. In addition, IDO overexpression has been closely tied to cancer metastasis: research in lung cancer cells reveals that higher IDO levels improve cell viability, whereas IDO inhibition diminishes it. In mouse models, administering lung cancer cells overexpressing IDO leads to more frequent metastases in the brain, liver, and bone [70]. These observations pinpoint IDO as a promising therapeutic target in ccRCC and other malignancies, warranting further exploration. Arginine metabolism is similarly disrupted in ccRCC, involving abnormalities in arginine transporters and metabolic enzymes, including arginase and arginine succinate synthase 1 (ASS1). Tumor cells often display reduced or missing ASS1 expression, an enzyme needed to convert citrulline into arginine, forcing cancer cells to rely on external arginine. Proteomic analyses of ccRCC biopsies support this dependency. Targeting arginine metabolism thus offers a potential therapeutic approach, as depriving tumor cells of this vital nutrient can suppress cancer progression. Research has shown that eliminating arginine selectively induces cell toxicity in ASS1-deficient tumors [71]. In summary, disrupted amino acid metabolism contribute to metabolic supremacy and tumor aggressiveness in renal cancer (Figure 2).
A particularly auspicious tactic targets the HIF-2α signaling pathway, a major downstream effector of the frequently mutated VHL tumor suppressor gene in ccRCC [90]. HIF-2α governs critical functions such as angiogenesis, cell proliferation, and metabolism, each substantially influencing tumor expansion and metastasis. Formerly deemed “undruggable” [91], HIF-2α has recently been shown to possess a structural vulnerability in its PAS-B domain. This discovery spurred the development of initial HIF-2α inhibitors like PT2399 and PT2385, which alter the PAS-B domain’s shape to block the formation of the HIF-2α/HIF-1β complex [92]. PT2399 has even surpassed sunitinib in certain models and remained effective against sunitinib-resistant tumors, although prolonged therapy can induce resistance via mutations in the binding site or HIF-1β [93], and it does not fully suppress all HIF-2α target genes. PT2385, meanwhile, showed a favorable safety profile and minimal toxicity in phase I trials, with a complete response observed in 2% of patients, partial responses in 12%, and stable disease in 52% [94]. In response to the shortcomings of these first-generation inhibitors, second-generation HIF-2α antagonists have been created, such as PT2977 (also known as MK-6482 or belzutifan) [95]. PT2977 targets a region adjacent to the PAS-B domain, triggering a conformational change that disrupts gene interactions. It also boasts low lipophilicity, high oral bioavailability, and an encouraging safety profile. In a phase II trial, a daily dose of 120 mg resulted in a 49% objective response rate among ccRCC patients, with primarily mild and manageable side effects [96, 97]. Consequently, newer HIF-2α inhibitors, particularly PT2977, have emerged as promising targeted therapeutics for ccRCC, offering improved potency and tolerability compared to older treatments.
Cancer cells also exploit glutamine metabolism to support energy generation, redox balance, and the synthesis of essential macromolecules. In ccRCC, GLS replenishes the TCA cycle and modestly drives cell proliferation [12]. The GLS inhibitor CB-839 has demonstrated strong anticancer activity in preclinical models. In animal studies, combining CB-839 with Everolimus, an mTOR inhibitor commonly used in ccRCC, enhanced antitumor efficacy. Clinical exploration of this combination, however, remains sparse, emphasizing the need for more extensive safety and effectiveness data [98, 99]. Furthermore, some cancers exhibit elevated arginine dependence due to deficient ASS1, thereby increasing their reliance on external arginine [100]. Since arginine is pivotal for nitric oxide production and protein biosynthesis, reducing circulating arginine through ADI-PEG20 (a PEG-conjugated arginine deaminase) has been proposed as a strategy to constrain tumor growth in ccRCC. That said, the re-expression of ASS1 may diminish its impact [12]. Clinical data point to good tolerance of ADI-PEG20 and suggest it may overcome drug resistance in cancers that rely heavily on arginine [101]. Additionally, encouraging results have been reported for ADI-PEG20 in non-small cell lung cancer, acute myeloid leukemia, and uveal melanoma [102, 103]. Further research will be crucial for refining combination regimens and determining how best to avert resistance. The enzyme IDO degrades tryptophan via the kynurenine pathway, contributing to an immunosuppressive tumor environment by lowering tryptophan levels, thereby impeding T-cell function and promoting metastasis [69]. IDO inhibition has thus become an appealing immunotherapeutic avenue. The selective IDO inhibitor Epacadostat was found in preclinical studies to enhance the response of tumor-specific T cells [104], though clinical outcomes have been mixed, showing toxicity issues and moderate efficacy at best. Early-phase trials combining Epacadostat with the PD-1 inhibitor pembrolizumab showed limited but notable antitumor responses in advanced solid tumors; however, more research is needed to fully establish its clinical benefit [105]. Meanwhile, Navoximod has displayed acceptable tolerability and moderate bioavailability at 800 mg twice daily. Although Navoximod monotherapy showed limited impact, pairing it with Atezolizumab produced encouraging safety profiles and measurable antitumor activity, with ongoing trials investigating its broader therapeutic potential [106-108]. Additional IDO inhibitors, such as KHK2455, LY3381916, and MK-7162, are in clinical studies to evaluate their safety and efficacy [67]. Moving forward, it will be essential to refine combination therapies and dosing strategies for IDO-targeted treatments. When considered alongside approaches like glycolysis inhibition, HIF-2α antagonism, and interventions involving lipid, glutamine, and arginine pathways, the growing range of metabolic therapies holds real promise for improving outcomes in ccRCC.
Genetic alterations in ccRCC also impact lipid metabolism, which is integral to tumor proliferation. FAS overexpression, a common finding, elevates intracellular fatty acid concentrations, fueling cancer growth and affecting post-translational modifications. Fatty acids are critical for both energy production and the maintenance of redox balance [109]. These insights have led researchers to propose inhibiting fatty acid synthesis as a therapeutic approach, supported by studies correlating greater FAS expression with higher tumor aggressiveness and worse clinical outcomes [110]. Preclinical evaluations indicate that the FAS inhibitor C75 can limit ccRCC cell proliferation and aggressiveness [111]. Another agent, TVB-2640, has shown promise in clinical contexts. A phase I investigation reported reduced fatty acid production in patients with non-small cell lung cancer, and follow-up trials in breast and ovarian cancers confirmed its efficacy and generally mild dermatological and ocular side effects [112]. TVB-2640 is currently undergoing evaluation in numerous cancer trials, including studies focused on ccRCC, suggesting that FAS inhibitors could eventually play a valuable role in treating this disease.
None.
Ethical policy
Non applicable.
Availability of data and materials
All data generated or analysed during this study are included in this publication.
Author contributions
Reham Gholam contributed to design of the work, data collection, and drafting the article. Muhammad Khalilzad was devoted to critical revision and final submission of the article.
Competing interests
The authors declare no competing interests.
Funding
None.
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