Emerging roles for the epigenetic modifiers PBRM1 SETD2 and BAP1 in clear cell renal cell carcinoma pathogenesis and prognosis beyond VHL

Abstract

Clear cell renal cell carcinoma (ccRCC) pathogenesis, which is traditionally centered on VHL inactivation, is critically driven by recurrent mutations in the epigenetic modifier genes PBRM1, SETD2, and BAP1 on chromosome 3p. These mutations define molecular subtypes with distinct clinical outcomes. PBRM1 loss (∼40%), a subunit of the SWI/SNF complex, is linked to a more indolent phenotype and potential sensitivity to antiangiogenic therapy as well as immune checkpoint inhibitor (ICI) resistance. SETD2 mutations (10–15%) cause genomic instability and are associated with aggressive features but may improve the ICI response. BAP1 mutation (10–15%) strongly predicts high-grade tumors, sarcomatoid differentiation, poor survival, and therapy resistance. The mutational status of these genes provides powerful prognostic and emerging predictive biomarkers. Future precision medicine strategies are evolving toward integrated multigene models and novel therapies targeting epigenetic vulnerabilities, such as synthetic lethality approaches and combination therapies, to improve ccRCC management.Furthermore, recent studies reveal that mutations in these epigenetic modifiers profoundly reshape the metabolic network of ccRCC by altering key pathways such as glycolysis, oxidative phosphorylation, and lipid metabolism. This dysregulation of the “epigenetic-metabolic axis” provides a novel mechanism underlying tumor heterogeneity, stemness, and differential treatment responses, opening new avenues for developing combination therapies that target metabolic vulnerabilities.

Introduction

Renal cell carcinoma (RCC) is a common urological malignancy, with ccRCC being its most prevalent histological subtype, accounting for approximately 75–80% of all cases [1]. For decades, the molecular pathogenesis of ccRCC has been predominantly attributed to inactivation of the von Hippel‒Lindau (VHL) tumor suppressor gene [2, 4], which is located on chromosome 3p25. The loss of functional VHL protein leads to the constitutive stabilization of hypoxia-inducible factors (HIFs) [2], even under normoxic conditions. The central role of the VHL-HIF axis has not only elucidated the biology of ccRCC but also paved the way for the development of highly effective antiangiogenic therapies [3, 4], revolutionizing the treatment landscape for advanced disease.

However, the VHL story is incomplete. While VHL inactivation is a nearly universal event in ccRCC (occurring in more than 90% of cases, either through mutation, deletion, or promoter hypermethylation), it alone is insufficient to cause cancer. This necessitates the accumulation of additional genetic hits. This necessitates the accumulation of additional genetic hits. Early work identified recurrent mutations in key epigenetic regulator genes on chromosome 3p [5]. This was conclusively confirmed and expanded by seminal studies, most notably those by The Cancer Genome Atlas (TCGA) Research Network [6]. These studies established that the most frequent and significant co-occurring genetic alterations in ccRCC are indeed found on chromosome 3p, implicating a cluster of crucial tumor suppressor genes adjacent to VHL.

This review focuses on the trio of epigenetic modifier genes—PBRM1 (polybromo-1), SETD2 (SET domain containing 2), and BAP1 (BRCA1 associated protein 1) [6]—located at 3p21.1‒p21.31, which represent the most commonly mutated genes in ccRCC after VHL itself. Their discovery marked a paradigm shift, highlighting that dysregulation of chromatin remodeling and histone modification is a fundamental hallmark of ccRCC, similar to dysregulated angiogenesis [7].

These genes are not mere passengers; they are pivotal drivers of tumor heterogeneity and clinical outcomes. These mutations are often mutually exclusive and define distinct molecular subtypes with markedly different pathological features and prognoses. For example, BAP1 mutations are strongly associated with high-grade, aggressive tumors and poor survival [8, 9, 10], whereas PBRM1 mutations often correlate with a more indolent phenotype [11]. In addition to their prognostic value, their potential as predictive biomarkers for response to emerging therapies, particularly immune checkpoint inhibitors [12, 13], and as harbingers of novel synthetic lethal therapeutic strategies is increasing.Notably, beyond chromatin regulation, ccRCC is fundamentally a metabolic disease characterized by profound reprogramming of energy metabolism, including enhanced glycolytic flux, impaired mitochondrial oxidative phosphorylation (OXPHOS), and dysregulated lipid metabolism [14, 15, 16]. This metabolic rewiring is central to tumor growth, survival, and adaptation. Critically, the functional inactivation of epigenetic modifiers represented by PBRM1, SETD2, and BAP1 not only directly alters chromatin states but also profoundly influences the reprogramming of energy and material metabolism in ccRCC by regulating downstream transcriptional programs [15, 17]. This tight coupling between epigenetic dysregulation and metabolic aberration acts as a synergistic driving force for malignant progression, representing a key to understanding ccRCC biology and developing novel therapeutics.

Biology of key epigenetic modifiers

The molecular profile of ccRCC extends far beyond VHL gene inactivation. Comprehensive genomic characterization, most notably by The Cancer Genome Atlas (TCGA) project, has definitively established epigenetic regulator genes—most frequently PBRM1, followed by SETD2 and BAP1—as among the most commonly mutated drivers in ccRCC [18]. These genes are clustered on the short arm of chromosome 3 (PBRM1 and SETD2 at 3p21, BAP1 at 3p21.1), adjacent to VHL (3p25). Deletion mapping studies confirm that they are predominantly inactivated through a combination of somatic mutation and loss of heterozygosity (LOH) affecting the entire 3p arm, the classic “second hit” mechanism in ccRCC pathogenesis [19]. The proteins encoded by these genes are master regulators of chromatin architecture and histone modification. Their collective inactivation profoundly dysregulates the cellular transcriptome and epigenome, serving as a pivotal driver of intra-tumoral heterogeneity and malignant progression [20].

PBRM1 (Polybromo-1)

PBRM1 is the second most frequently mutated gene in ccRCC and is altered in approximately 40% of tumors [18]. This gene encodes the BAF180 protein, a key specific subunit of the SWI/SNF (or PBAF) chromatin remodeling complex [21].This complex acts as a large multiprotein machine that utilizes the energy from ATP hydrolysis to slide nucleosomes, thereby regulating chromatin accessibility and influencing gene transcription [21]. The PBRM1 protein contains multiple bromodomains, which specifically recognize and bind to acetylated histone tails, recruiting the entire complex to specific active regions of chromatin; this function is crucial for its role [22]. In ccRCC, the mutation spectrum of PBRM1 is predominantly characterized by nonsense mutations, frameshift mutations, and splice site mutations that primarily lead to a complete loss of protein function (null allele) [23], with missense mutations often clustering in the bromodomains, particularly BD2 and BD4 [21, 22].Inactivation of PBRM1 leads to a series of profound biological consequences. First, it causes impaired SWI/SNF complex function, leading to dysregulated chromatin remodeling, which subsequently alters the global transcriptome [20, 21]. Studies have shown that the re-expression of PBRM1 results in the upregulation of genes involved in cellular adhesion, carbohydrate metabolism, and apoptosis and the downregulation of genes involved in cell division, highlighting its role as a tumor suppressor [24]. Second, PBRM1 loss amplifies the HIF response caused by VHL loss, enhancing the hypoxic signaling pathway associated with tumorigenesis [25]. Furthermore, PBRM1 interacts with the p53 pathway; activation of p53 can reduce PBRM1 protein levels via proteasomal degradation, suggesting a complex regulatory relationship between the two in carcinogenesis [26].With respect to the cellular phenotype, the loss of PBRM1 is associated with cancer progression, and its loss of expression is correlated with advanced tumor stage, low differentiation grade, and poor patient outcome [27]. Notably, unlike BAP1 mutations, which typically predict an aggressive clinical course, PBRM1 mutations are considered, in some contexts, to be associated with a relatively better prognosis and improved response to targeted therapies (such as VEGF pathway inhibitors), although their exact prognostic role remains controversial [11, 28–30]. However, PBRM1 loss is also associated with a nonimmunogenic tumor phenotype and resistance to immune checkpoint inhibitors, presenting new therapeutic challenges [31].For PBRM1-mutated tumors, there are currently no direct targeted drugs available, but synthetic lethality screening has revealed that DNMT inhibitors (e.g., 5-fluoro-2′-deoxycytidine) selectively inhibit the growth of PBRM1-deficient renal cancer cells, suggesting a new potential therapeutic direction [32] (Fig. 1).

Fig. 1.

Mechanisms of PBRM1 loss-mediated tumor immune escape. Loss of PBRM1, a key subunit of the SWI/SNF (PBAF) chromatin remodeling complex, leads to impaired IFN-γ signaling, characterized by reduced binding to the IFNGR2 promoter, decreased STAT1 phosphorylation, and suppressed expression of downstream target genes. Furthermore, PBRM1 deficiency alters the metabolic state of tumor cells (e.g., enhanced glycolysis) and may affect the expression of antigen presentation-related genes. These changes collectively shape an immunosuppressive tumor microenvironment, featuring attenuated cytotoxic T cell function and dysregulated immune checkpoint molecule expression, ultimately contributing to resistance to immune checkpoint inhibitors (ICIs)

SETD2 (SET domain containing 2)

SETD2 is a critical histone methyltransferase that functions as the sole enzyme responsible for catalyzing H3 lysine 36 trimethylation (H3K36me3) in mammals [33, 34]. This histone mark is intricately associated with active transcription, where it guides transcriptional elongation, maintains fidelity, regulates RNA splicing, and facilitates DNA damage repair [35]. In ccRCC, SETD2 is mutated in approximately 10–15% of cases, with a notably higher frequency observed in metastatic tumors, reaching 24.7% [18, 36]. The mutation spectrum is characterized predominantly by loss-of-function truncating mutations (nonsense/frameshift), similar to PBRM1, as well as missense mutations that directly impair its methyltransferase activity by targeting the catalytic SET domain [14, 37]. The inactivation of SETD2 leads to profound biological consequences. The most direct effect is a genome-wide loss of H3K36me3 [38], which causes a global alteration of the epigenetic landscape and disrupts normal gene expression programs [39]. This epigenetic dysregulation promotes a hypermethylated DNA phenotype and activates enhancers that drive oncogenic transcriptional output [39, 40]. Furthermore, SETD2 deficiency is a major driver of genomic instability; the loss of H3K36me3 impairs DNA damage repair mechanisms, leading to increased replication stress, chromosomal aberrations [38], and elevated mutation burden, thereby fostering tumor evolution and heterogeneity [16]. SETD2 loss also impacts cellular metabolism and immune recognition. It can induce a metabolic switch toward enhanced oxidative phosphorylation and promote purine nucleotide biosynthesis via the LEDGF-H3R17me2a axis [15, 41]. From a clinical perspective, SETD2 mutations and the consequent loss of H3K36me3 are consistently associated with aggressive disease features, including larger tumor size and advanced stage, and increased risk of cancer-specific death, establishing its role as a marker of poor prognosis [42–44].

Therapeutically, SETD2 mutations can confer vulnerabilities. They are associated with a favorable response to immune checkpoint blockade (ICB) [31, 45], and SETD2 loss synergizes with ATR inhibition to enhance cGAS signaling and immune cell infiltration, suggesting potential combination strategies [46, 47]. Additionally, SETD2-deficient cells are sensitive to combination therapies involving DNA hypomethylating agents and PARP inhibitors, highlighting a synthetic lethal approach for this molecular subset [48].

BAP1 (BRCA1 associated protein 1)

The BAP1 gene encodes a deubiquitinase that functions as a critical tumor suppressor, with its normal activity centered on the removal of monoubiquitination from histone H2A (H2AK119ub) [49]. By forming the PR-DUB complex with ASXL proteins, BAP1 counteracts the repressive function of Polycomb complexes, thereby facilitating the activation of specific genes involved in tumor suppression and differentiation [49, 50]. Additionally, BAP1 participates in other essential cellular processes, including cell cycle regulation and the DNA damage response [51, 52]. In ccRCC, BAP1 is mutated in approximately 10–15% of cases, with the mutation spectrum encompassing truncating mutations and missense mutations, the latter often clustering within the catalytic UCH domain that is essential for its deubiquitinase activity [18, 53]. The inactivation of BAP1 leads to severe biological consequences.First, H2AK119ub causes a transcriptional imbalance due to genome-wide accumulation of H2AK119ub, which reinforces Polycomb-mediated gene silencing and leads to the sustained repression of key differentiation genes and tumor suppressors [49]. This promotes a dedifferentiated and highly aggressive phenotype, as BAP1-mutated tumors are strongly associated with adverse pathological features such as high Fuhrman grade, sarcomatoid dedifferentiation, tumor necrosis, and advanced pathological stage [53, 54]. Consequently, among the trios of epigenetic modifiers (PBRM1, SETD2, BAP1), BAP1 mutation serves as the most definitive and powerful indicator of poor prognosis, with its loss being an independent marker significantly associated with shorter disease-free survival, overall survival, and an increased risk of cancer-specific death in ccRCC patients [54–56].

Epigenetic modifiers and metabolic reprogramming in ccRCC

Beyond their canonical roles in chromatin biology including chromatin remodeling and gene expression regulation, the inactivation of PBRM1, SETD2, and BAP1 is now recognized as a pivotal upstream event and key modulator that orchestrates extensive metabolic reprogramming in clear cell renal cell carcinoma (ccRCC), a defining hallmark of this cancer type [50, 57]. Metabolic aberrations in ccRCC are characteristically driven by the VHL-HIF axis, featuring enhanced glycolytic flux, impaired mitochondrial oxidative phosphorylation (OXPHOS), and dysregulated lipid metabolism [16, 58], and the inactivation of these epigenetic modifiers further refines and amplifies these metabolic programs, contributing to tumor heterogeneity, therapy response, and microenvironmental crosstalk [58, 59]. Far from a passive consequence of tumorigenesis, this epigenetic modifier-mediated metabolic reprogramming acts as an active driver of tumor evolution, with the specific metabolic alterations induced by each mutant gene converging to impact a core cancer hallmark: the acquisition and maintenance of stem-like properties. This intricate interplay defines an “epigenetic-metabolic-stemness” axis, wherein epigenetic lesions dictate distinct metabolic configurations that in turn fuel tumor initiation, plasticity, therapy resistance, immune evasion, and further exacerbate the aforementioned tumor heterogeneity and microenvironmental crosstalk. Understanding this axis is therefore essential for deciphering the underlying biology of ccRCC and developing mechanism-based therapeutic strategies for the disease.

PBRM1 loss: amplifying the glycolytic phenotype and niche for stemness

The metabolic impact of PBRM1 loss is intrinsically linked to its role in modulating the HIF response. Mechanistically, PBRM1, as part of the PBAF complex, normally constrains the transcriptional activity of HIF even in VHL-deficient cells [25]. Its inactivation leads to derepression of HIF target genes, resulting in hyperactivation of glycolysis and anaerobic metabolism [14, 40]. This creates a self-reinforcing cycle: a glycolytic flux provides not only ATP and biomass but also generates metabolites like lactate and acetyl-CoA that can further influence histone acetylation and gene expression [60, 61].

Connection to Stemness: This heightened glycolytic state is not merely proliferative. A glycolytic metabolism is a hallmark of many cancer stem cells (CSCs), as it supports rapid energy production and provides precursors for macromolecular synthesis in fluctuating microenvironments. The lactate-rich microenvironment resulting from glycolysis can also promote an immunosuppressive niche and activate signaling pathways (e.g., TGF-β) associated with epithelial-mesenchymal transition (EMT) and stemness [62]. Therefore, PBRM1 loss, by locking cells into a HIF-driven glycolytic mode, may create and sustain a metabolic niche favorable for CSC maintenance and phenotypic plasticity, explaining its association with certain indolent yet persistent and therapy-resistant tumor features.

SETD2 mutation: orchestrating a pro-survival metabolic switch with genomic consequences

SETD2 Mutation and Metabolic Switching. In contrast to other epigenetic modifier aberrations, SETD2 deficiency triggers a complex and distinct metabolic rewiring in ccRCC, driven by the global loss of H3K36me3 which dysregulates genes governing mitochondrial function and nucleotide metabolism [15]. Proteomic and metabolomic studies confirm that SETD2-deficient ccRCC cells undergo a compensatory metabolic switch characterized by enhanced oxidative phosphorylation (OXPHOS) capacity—an adaptive shift occurring within the overall glycolytic landscape of ccRCC that confers survival advantages under stress conditions such as nutrient deprivation or therapeutic intervention [15]. Additionally, SETD2 loss drives de novo nucleotide biosynthesis, including boosted de novo purine synthesis via the LEDGF/H3R17me2a axis [15, 38, 41], which supplies critical materials for DNA replication and repair and aligns with its established role in promoting genomic instability [38, 41].

Connection to Stemness and Aggression: Enhanced OXPHOS is increasingly linked to a distinct, more quiescent yet highly resilient cancer stem cell (CSC) population across various cancer types, and the augmented nucleotide synthesis capacity in SETD2-deficient cells supports the rapid DNA repair required for clonal expansion under genomic stress. Consequently, SETD2-deficient ccRCC tumors likely harbor CSCs that are metabolically primed for survival, self-renewal, and adaptive plasticity, which directly contributes to the observed genomic instability, tumor heterogeneity, and aggressive clinical course of these lesions. This unique metabolic reprogramming renders SETD2-deficient tumors simultaneously vulnerable to targeted interventions such as OXPHOS inhibitors and inherently resilient to stress and therapeutic challenge(Figure 2B).

Fig. 2.

Associations of BAP1 and SETD2 mutations with malignant progression in clear cell renal cell carcinoma. A BAP1 loss promotes a dedifferentiated, aggressive phenotype. As a deubiquitinase, functional BAP1 normally removes monoubiquitination from histone H2A (H2AK119ub), counteracting Polycomb-mediated gene silencing. Loss of BAP1 leads to global accumulation of H2AK119ub, resulting in sustained repression of key differentiation genes and tumor suppressors, which drives high-grade histology, sarcomatoid/rhabdoid features, and poor prognosis. B SETD2 deficiency drives genomic instability and metabolic reprogramming. SETD2 is the sole enzyme catalyzing H3 lysine 36 trimethylation (H3K36me3). Its loss leads to global depletion of H3K36me3, disrupting transcriptional fidelity, RNA splicing, and DNA damage repair. This results in increased genomic instability, replication stress, and a metabolic switch towards enhanced oxidative phosphorylation (OXPHOS) and nucleotide synthesis. C Cumulative impact on tumor evolution. Mutations in epigenetic regulators like BAP1 and SETD2, often co-occurring with chromosome 3p loss, are key drivers of intratumoral heterogeneity, clonal evolution, and the acquisition of aggressive traits and therapy resistance in ccRCC

BAP1 inactivation: driving a dedifferentiated state through lipid metabolism and repressive silencing

BAP1 functions as a global transcriptional regulator via histone deubiquitination [19, 63], and its loss leads to broad transcriptional silencing through H2AK119ub accumulation, a molecular change strongly associated with highly aggressive, dedifferentiated (e.g., sarcomatoid) tumor phenotypes in ccRCC [20, 66]. This repressive transcriptional landscape extensively rewires lipid metabolism— a core feature of ccRCC linked to tumor aggressiveness [67]— by upregulating genes related to lipid uptake (e.g., CD36) and storage while downregulating those governing fatty acid oxidation [16, 69]. The resulting lipid droplet accumulation is not merely inert energy storage; these structures act as key signaling hubs and energy reservoirs, and their abundance correlates strongly with high-grade, sarcomatoid, and metastatic ccRCC phenotypes [16, 69]. Notably, lipid metabolism is critical for cancer stem cell (CSC) function: lipid droplets can regulate oxidative stress, supply energy during cellular dormancy, and their constituent lipids (e.g., prostaglandins) activate pro-stemness signaling pathways such as Wnt/β-catenin. This metabolic reprogramming underpins the profound dedifferentiation phenotype (sarcomatoid/rhabdoid features) of BAP1-mutant tumors, an extreme form of cellular plasticity akin to stem-like reprogramming. Thus, BAP1 loss potentiates a stem-like, dedifferentiated state through pervasive gene repression that drives a pro-lipid anabolic metabolic program, a mechanism that aligns perfectly with BAP1 mutation being the strongest marker of ccRCC aggressiveness and poor clinical outcome. This link between BAP1 inactivation, lipid metabolic reprogramming and malignant progression is further supported by the identification of BAP1 mutation as a key determinant of late metastasis in ccRCC [70], underscoring its role in driving progressive disease states via metabolic adaptation. Additionally, the immunosuppressive tumor microenvironment of BAP1-mutant ccRCC may involve metabolic competition, a process that further contributes to immunotherapy resistance in these tumors (Figure 2A) [71].

Therapeutic implications: targeting the axis

The metabolic alterations driven by these epigenetic defects in ccRCC present novel and actionable therapeutic vulnerabilities, with tailored strategies emerging for each mutant subtype. PBRM1-deficient tumors, characterized by reinforced glycolysis, may be effectively targeted with glycolytic inhibitors (e.g., HK2 or LDHA inhibitors) in combination regimens—including agents that target the resultant CSC niche (e.g., anti-TGF-β) or reverse epigenetic silencing (e.g., DNMT inhibitors) [72]. SETD2-mutant tumors with enhanced OXPHOS and de novo nucleotide synthesis are susceptible to metabolic pathway inhibitors (e.g., complex I inhibitors/metformin derivatives or purine synthesis antagonists), and synthetic lethal approaches combining these agents with DNA damage response inhibitors (e.g., PARPi, ATRi) to exploit concomitant genomic instability represent a rational therapeutic avenue [48, 73]. For BAP1-deficient tumors, targeting the rewired lipid metabolism (e.g., with fatty acid synthase or CD36 inhibitors) or the downstream consequences of dedifferentiation (e.g., EMT or stemness pathway inhibitors) is promising, and these strategies are particularly impactful when combined with immunotherapies (e.g., IDO or adenosine pathway inhibitors) to counteract the tumor’s immunosuppressive metabolic microenvironment [74].

Most importantly, the intersection of epigenetic dysregulation, metabolic rewiring, and stemness properties—the defined “epigenetic-metabolic-stemness” axis—represents a critical frontier for therapeutic discovery in ccRCC. Targeting the specific metabolic dependencies of epigenetic-mutant ccRCC, particularly those that sustain CSC populations, holds great potential to overcome therapy resistance and improve clinical outcomes [39, 62]. This axis reveals coordinated vulnerabilities that enable the design of combinatorial therapies tailored to the unique molecular and metabolic features of each epigenetic subtype, moving beyond single-agent approaches to precision intervention.

To fully realize this potential, future research integrating multi-omics data is essential to comprehensively define these metabolic subtypes [84], elucidate the precise mechanistic links between epigenetic lesions, metabolic reprogramming and stemness, and ultimately translate these findings into robust, clinically applicable precision therapies for ccRCC patients (Table 1).

Table 1.

The Epigenetic-Metabolic-Stemness Axis in ccRCC: Mechanisms and Implications

Epigenetic lesion	PBRM1 loss	SETD2 mutation	BAP1 mutation
Primary chromatin mechanism	Loss of PBAF complex function →Derepression of HIF transcriptional targets [25, 36].	Loss of H3K36me3 →Dysregulation of elongation-coupled processes(transcription, splicing, repair) [38, 39].	Loss of H2AK119ub deubiquitination →Genome-wide Polycomb-mediated silencingof differentiation & tumor suppressor genes [49, 63].
Core metabolic reprogramming	Hyperactive glycolysis (“Warburg effect”). • Increased glucose uptake & lactate production. • Precursor supply for biosynthesis [14, 40].	Metabolic switch to OXPHOS & enhanced nucleotide synthesis. • Increased mitochondrial respiration. • Boostedde novopurine synthesis via LEDGF/H3R17me2a [15, 41].	Dysregulated lipid metabolism & anabolic storage. • Enhanced lipid uptake (e.g., CD36) and droplet formation. • Repression of fatty acid oxidation [16, 69].
Link to stemness & tumor behavior	• Creates aglycolytic nichethat supports CSC maintenance and plasticity. • Lactate output fosters an immunosuppressive TME. • Associated with apersistent, therapy-resistantphenotype [62].	• Fuels genomic instabilityand clonal evolution. • OXPHOS dependency may maintain aquiescent, resilient CSC pool. • Underpinsaggressive, heterogeneoustumors with poor prognosis.	•Drives extreme dedifferentiation(sarcomatoid/rhabdoid features). • Lipid metabolism supportsCSC signaling, survival, and immune evasion. • The strongest correlate ofrapid progression and poor survival.
Potential Therapeutic Vulnerabilities	•Glycolysis inhibitors(e.g., HK2/LDHA inhibitors). •DNMT inhibitors(synthetic lethal). • Agents targeting the resulting immunosuppressive niche (e.g., TGF-β inhibitors).	•OXPHOS inhibitors(e.g., Complex I inhibitors like metformin analogs). •Nucleotide synthesis antagonists. •Synthetic lethalcombinations: PARPi/ATRi + DNA hypomethylating agents [48].	•Lipid metabolism inhibitors(e.g., FASN or CD36 inhibitors). •BET inhibitors(synthetic lethal) [94]. •Immunotherapy combinationsto reverse associated immunosuppression.

Future perspectives

Future research must move beyond correlative studies to functional validation of this axis. This includes using isogenic cell models to define causal metabolic changes, tracing the fate of metabolically defined subpopulations in vivo, and integrating single-cell multi-omics (epigenetic, transcriptomic, metabolomic) to map the heterogeneity of this axis within tumors. Clinically, developing non-invasive imaging (e.g., hyperpolarized MRI) or circulating biomarkers to assess tumor metabolic subtype will be crucial for translating these insights into personalized, effective combination therapies that concurrently disrupt epigenetic drivers, metabolic dependencies, and the stem cell reservoir.

Correlation with clinicopathological features

Extensive research on PBRM1, SETD2, and BAP1 has not only elucidated their biological functions but also established them as crucial prognostic biomarkers. The mutation status of these genes demonstrates significant and patterned correlations with multiple key clinicopathological features of ccRCC, providing a powerful molecular tool for patient risk stratification and personalized management.

PBRM1 mutation: a milk phenotype?

In contrast to those of BAP1, the clinicopathological characteristics of PBRM1 mutations are often, although not absolutely, associated with a relatively indolent disease course, forming a fascinating “molecular dichotomy“ [21, 75].With respect to tumor grade and stage, PBRM1 mutations tend to be more common in low-grade (G1/G2) and localized (pT1/pT2) tumors [27]. Loss of PBRM1 expression has been correlated with advanced tumor stage and low differentiation grade in some studies, yet its mutation is frequently identified in a context distinct from aggressive features [27]. A key aspect of this dichotomy is mutual exclusivity; PBRM1 and BAP1 mutations often demonstrate a mutually exclusive pattern within tumors, which partially explains their divergent clinical phenotypes and the association of PBRM1 with a less aggressive subgroup [21, 55, 76]. Concerning patient survival, a significant body of evidence suggests that PBRM1 mutation is linked to better prognosis and longer survival in certain contexts [21, 75]. For example, in a study of metastatic RCC, PBRM1 mutations were associated with longer progression-free survival in patients treated with first-line everolimus [29]. However, this association is not without controversy and complexity. Some studies have reported no significant independent associations between PBRM1 and overall survival, cancer-specific survival, or recurrence-free survival after adjusting for standard clinicopathological parameters [77]. The prognostic impact appears context dependent, as the concomitant loss of both PBRM1 and BAP1 protein expression is associated with a significantly greater risk of cancer-specific death and disease recurrence [55] than either loss alone [9]. Furthermore, PBRM1 inactivation defines a nonimmunogenic tumor phenotype associated with resistance to ICB, suggesting that its prognostic value is nuanced and may be dependent on the treatment modality [31]. In summary, PBRM1 mutations tend to define a ccRCC subtype with lower aggressiveness and a relatively more favorable prognosis, but its role is complex and can be influenced by comutations, particularly with BAP1, and the specific therapeutic context [9, 21, 31, 75].

SETD2 mutation: an emerging aggressive player

The clinical relevance of SETD2 mutations lies between those of BAP1 and PBRM1, with a growing body of evidence associating SETD2 mutations with aggressive disease features. In terms of tumor grade and stage, SETD2 mutations are positively correlated with more advanced disease. They are found more frequently in larger tumors, with each 1 cm increase in tumor size associated with increased odds of harboring a SETD2 mutation [78]. Furthermore, low expression of SETD2 is significantly associated with advanced pathological T stage (pT stage) in nonmetastatic ccRCC [44]. With respect to patient survival, SETD2 mutations are consistently identified as an independent predictor of poor prognosis. Multiple studies across distinct cohorts have shown that SETD2 mutations are associated with poor cancer-specific survival (CSS) [37]. The loss of the H3K36me3 mark, which is the direct epigenetic consequence of SETD2 inactivation, is a powerful prognostic indicator; patients with H3K36me3-negative tumors have a greater than twofold increased risk of renal cell carcinoma-specific death compared with those with H3K36me3-positive tumors [42]. The underlying mechanism for this aggressive phenotype likely stems from its core biological functions. SETD2 deficiency drives genomic instability through impaired DNA damage repair, promoting replication stress and chromosomal aberrations, which fuel tumor evolution, heterogeneity, and metastatic potential [39, 48]. While this genomic instability may subsequently enhance responsiveness to immunotherapy in some contexts, in traditional patient cohorts not receiving such treatments, it manifests as increased tumor aggressiveness and poorer overall outcomes [37, 46].

BAP1 mutation: the archetype of aggressive disease

BAP1 mutation is widely regarded as the archetype of aggressive disease in ccRCC, with consistent and robust evidence establishing its association with poor prognosis, making it one of the strongest molecular predictors of outcome in ccRCC. With respect to tumor grade, BAP1 mutation was significantly correlated with high Fuhrman nuclear grade (G3/G4). Tumors harboring BAP1 mutations often exhibit marked nuclear pleomorphism and high-grade morphological features. Furthermore, BAP1 loss is a key driver of sarcomatoid and rhabdoid differentiation, which can be assisted by detecting the loss of BAP1 protein expression via immunohistochemistry [79, 80]. In terms of tumor stage, BAP1 mutation is strongly associated with a higher pathological TNM stage, including features such as tumor necrosis, invasion into perinephric fat (pT3a), venous involvement (pT3b/c), and a higher frequency of distant metastasis (M1 disease) at initial presentation [10]. With respect to patient survival, BAP1 mutation serves as an independent negative predictor for overall survival, cancer-specific survival, and progression-free survival [54, 56]. Large cohort studies have demonstrated that patients with BAP1-mutant tumors have a significantly increased hazard ratio for death and substantially shorter median survival times than their wild-type counterparts do [37]. This association remained significant even after adjusting for conventional factors such as age, grade, and stage [54, 56]. In summary, BAP1 mutation defines a molecular subtype of ccRCC characterized by high aggressiveness, rapid progression, and poor prognosis.

Composite models and future directions

Current research on ccRCC is shifting from the isolated analysis of individual genes toward the construction of integrated multigene prognostic models [81]. This paradigm shift aims to achieve more precise molecular subtyping and risk stratification, focusing on the key epigenetic modifiers PBRM1, SETD2, and BAP1.

Substantial evidence confirms that the combinatorial mutation status of these three genes defines distinct ccRCC molecular subtypes with significantly divergent clinical outcomes. Among them, BAP1 mutations are widely recognized as the strongest molecular marker of high-risk disease. Its presence often dictates a poor prognosis and is strongly associated with high-grade tumors, sarcomatoid differentiation, and markedly inferior survival rates [37, 54, 56]. In contrast, PBRM1 mutations have been associated with relatively low-risk disease characteristics in some studies, particularly when cooccurring with wild-type BAP1 [55]. However, the prognostic value of PBRM1 remains controversial, and its concomitant loss of BAP1 significantly increases the risk of cancer-specific death and disease recurrence [9]. SETD2 mutations are typically categorized within an intermediate-risk group. The inactivation of SETD2, which leads to loss of H3K36me3, is linked to defects in DNA repair [38], distinct alterations in the tumor immune microenvironment [46], and poor survival outcomes [42].

The clinicopathological correlations of these key epigenetic modifiers are succinctly summarized in the table below, powerfully illustrating their roles not as mere passenger mutations but as pivotal drivers of clinical disease behavior with profound prognostic utility (Table 2).

Table 2.

Summary of correlations between PBRM1, SETD2, and BAP1 mutations and clinicopathological features

Feature	PBRM1 mutation	SETD2 mutation	BAP1 mutation
Tumor grade	More frequent in low-grade (G1/G2) tumors	Positively correlated with high grade (G3/G4)	Strongly associated with high grade (G3/G4)
Tumor stage	More common in localized (pT1/pT2) disease	Positively correlated with advanced stage (pT3/pT4)	Strongly associated with advanced stage (pT3/pT4)
Histological features	Association not firmly established	Linked to tumor evolution and heterogeneity	Strongly associated with sarcomatoid/rhabdoid differentiation
Patient survival	Associated with better survival in certain contexts	Shorter cancer-specific survival (CSS)	Significantly shorter overall and cancer-specific survival
Prognostic value	Complex and context-dependent predictor	Independent negative predictor	Strongest independent negative predictor

These findings have collectively informed the development of multigene clinical stratification strategies. A representative model classifies patients into a low-risk group (PBRM1mut/BAP1wt/SETD2wt), a high-risk group (BAP1mut, often irrespective of other gene status), and an intermediate-risk group (encompassing SETD2mut or other combinations). This model, which integrates PBRM1 and BAP1 protein expression, has been demonstrated to identify four patient subgroups with significantly divergent clinical outcomes [55].

Despite this promising outlook, the development and application of such composite models face significant challenges. A primary imperative is the rigorous validation of these models in prospective, large-scale cohorts to ensure their robustness and generalizability. Furthermore, translating these molecular subtypes—largely derived from retrospective research—into standardized diagnostic workflows and decision-making tools for routine clinical practice is a critical step for realizing precision medicine and represents a key direction for future development.

Potential as predictive biomarkers

As clear cell renal cell carcinoma (ccRCC) treatment has entered the era of targeted therapy and immunotherapy, therapeutic options have become increasingly diverse. However, response rates remain inconsistent and lack reliable selection criteria. Mutations in PBRM1, SETD2, and BAP1 significantly influence tumor sensitivity to different treatment approaches by shaping unique biological characteristics, making them highly promising predictive biomarkers.

Predicting response to immune checkpoint inhibitors (ICIs)

The relationship between PBRM1 mutation status and the response to immune checkpoint inhibitors represents one of the most data-rich and promising areas in this field of research. Clinical observations from exploratory analyses of multiple retrospective studies and large-scale clinical trials suggest that patients with advanced ccRCC harboring PBRM1 mutations may derive significant survival benefits from ICI therapy [31, 45], whether as monotherapy or in combination regimens. The objective response rates and progression-free survival rates of these patients often appear superior to those of patients with PBRM1 wild-type tumors [82, 85]. The underlying mechanisms for this potential sensitization are thought to involve significant alterations in the tumor immune microenvironment. PBRM1 loss leads to dysfunction of the PBAF chromatin-remodeling complex, which can subsequently define a nonimmunogenic tumor phenotype associated with checkpoint inhibitor resistance [31]. Mechanistically, this PBRM1 deficiency reduces the binding of the BRG1 subunit to the promoter of interferon-gamma receptor 2 [31], thereby decreasing STAT1 phosphorylation and the expression of downstream IFNγ target genes and effectively blunting the cytotoxic T-cell response [31]. Conversely, other evidence points toward PBRM1 loss creating a more inflamed microenvironment, which has been associated with the recruitment of distinct immune cell populations and the regulation of specific immune-related genes (IRGs). A prognostic model constructed on the basis of PBRM1-associated IRGs demonstrated efficacy in stratifying patients, potentially facilitating future immunotherapeutic strategies [81]. This apparent paradox—where PBRM1 loss can simultaneously impair specific interferon signaling yet is associated with clinical benefit in some cohorts—highlights the complexity of the immunomodulatory functions of chromatin remodelers and underscores the need for further investigation to reconcile these mechanisms and identify reliable predictive biomarkers.

Unlike PBRM1 mutations, BAP1 mutations are generally associated with a poorer response to ICI therapy. This is a critical consideration in the context of its aggressive biology. Clinical observations suggest that despite potentially conferring a high tumor mutational burden, the formidable tumor aggressiveness and profoundly immunosuppressive microenvironment associated with BAP1 mutations likely negate this potential advantage [31, 71]. The underlying mechanisms for this resistance are multifaceted. First, BAP1-mutant ccRCC fosters a highly immunosuppressive tumor microenvironment. A key feature is the increased expression of C-C chemokine receptor 5 (CCR5) and its ligands by tumor cells. These ligands recruit CCR5⁺ regulatory T cells (Tregs) to the tumor site and upregulate programmed cell death ligand 1 (PD-L1) expression, actively creating an immune-suppressive niche that inhibits effective antitumor immunity [45, 71]. Second, the rapid progression of BAP1-deficient tumors is a significant factor. These tumors exhibit the fastest median growth rate among genetically defined renal tumors, indicating their exceptionally aggressive nature [86]. Consequently, even if an ICI eventually triggers an immune response, the kinetics of this response may be outpaced by the swift clinical progression of the disease, often manifesting as primary resistance or early disease progression in clinical assessments.

SETD2 mutations in RCC have emerged as significant potential biomarkers for predicting the response to ICIs, primarily by inducing genomic instability and altering the tumor immune microenvironment. Clinical observations indicate that loss-of-function SETD2 mutations promote branched tumor evolution and replication stress, leading to increased genomic heterogeneity and increased tumor mutational burden (TMB) A high TMB is a well-established predictor of ICI response across multiple cancer types [15, 36, 38]. The underlying mechanisms largely involve neoantigen generation: SETD2 mutation-induced genomic instability and epigenetic dysregulation (such as loss of H3K36me3) can increase tumor-specific mutations, thereby generating more neoantigens. This enhances tumor immunogenicity, making cancer cells more recognizable to and attackable by T cells [39, 46, 87]. Furthermore, studies have confirmed that SETD2 mutations are associated with altered patterns of immune cell infiltration, for example, significantly decreased levels of FOXP3 + T cells in the tumor core, stroma, and tumor-stroma interface, which may optimize the efficacy of ICI therapy [87]. Notably, in patients with metastatic RCC, SETD2 mutations are associated with a relatively high response rate and prolonged overall survival following ICI treatment [46]. However, direct clinical data validating SETD2 mutations as a standalone predictor of ICI efficacy remain less abundant than data for genes such as PBRM1 and BAP1. Despite this, the mechanistic rationale—suggesting an indirect role via high TMB and remodeling of the immune microenvironment—is robust, positioning SETD2 as a key focus for future prospective studies and the validation of personalized immunotherapy strategies [46, 88].

Predicting the response to antiangiogenic targeted therapy (VEGFR-TKIs)

In predicting the response of RCC to antiangiogenic targeted therapies such as VEGFR-TKIs, the two commonly comutated genes, BAP1 and PBRM1, play complex and often opposing roles, with predictive patterns gradually becoming clearer. BAP1 mutations are typically associated with a more aggressive tumor phenotype and poor prognosis, and some clinical evidence suggests that they may also confer primary resistance to VEGFR-TKIs. For example, in a randomized trial comparing first-line everolimus (an mTOR inhibitor) and sunitinib (a VEGFR-TKI) [29], BAP1 mutation was associated with a shorter median progression-free survival (PFS) in patients receiving first-line everolimus (4.9 vs. 10.5 months) [29]. Although these data pertain specifically to an mTOR inhibitor, they suggest that BAP1-mutated tumors are resistant to certain targeted drugs. The underlying mechanisms may be related to the chromosomal instability caused by BAP1 loss and its remodeling of the tumor microenvironment (e.g., promoting immunosuppression), which could diminish the efficacy of antiangiogenic therapy [63, 71].

Conversely, PBRM1 mutations tend to potentially increase sensitivity to VEGFR-TKIs. Mechanistically, upon functional loss, PBRM1, a subunit of the SWI/SNF chromatin remodeling complex, amplifies the HIF transcriptional response in VHL-deficient cells [18], potentially making tumor cells more dependent on and sensitive to VEGFR-TKIs that target the downstream angiogenic pathways of HIF. Clinical observations support this hypothesis; in patients with metastatic renal cell carcinoma, PBRM1 mutation was associated with longer progression-free survival when patients were treated with VEGF pathway-targeted therapy [29]. Furthermore, some studies have shown that coexisting mutations in PBRM1 and KDM5C are associated with increased tumor angiogenesis and a better response to antiangiogenic therapy [89].

Despite the promising nature of these patterns, research on predictive biomarkers in the field of targeted therapy generally lags behind that of immunotherapy. The inactivation status of the VHL gene itself has not been proven to be an effective predictive marker for the response to VEGFR-TKIs. Current predictive data for PBRM1 and BAP1 mostly originate from retrospective analyses or subgroup analyses with limited sample sizes, and the level of evidence needs improvement [29, 30]. Therefore, validating these findings in prospective, large-scale clinical trials is crucial for establishing the value of PBRM1 and BAP1 mutation status in guiding personalized targeted therapy.

Integrated application and future perspectives: toward precision medicine

The paradigm of precision medicine in RCC is shifting from reliance on single biomarkers toward the construction of composite biomarker models that integrate mutational information from key genes such as SETD2, BAP1, and PBRM1 to guide clinical decision-making more precisely. Future treatment strategies will increasingly depend on molecular subtyping based on these models.

1. The “PBRM1mut/BAP1wt” model: Tumors in this category often exhibit a relatively favorable prognostic profile. PBRM1 loss is associated with specific alterations in the immune microenvironment, potentially defining a nonimmunogenic phenotype [31]. Consequently, these patients might be candidates for ICI monotherapy, although their response rates could be limited by attenuated IFNγ signaling associated with PBRM1 deficiency [31]. Further research is needed to confirm the optimal immunotherapy regimen for this group.

2. The “BAP1mut” model: BAP1 mutation is strongly linked to highly aggressive tumor biology, including high histological grade, rapid growth rate, and poor prognosis [54, 86]. The tumor microenvironment is often immunosuppressive; for example, regulatory T cells are recruited via the CCR5 pathway, and PD-L1 expression is upregulated [71]. Therefore, these patients may require more aggressive first-line treatment. Therapeutic strategies might lean toward VEGFR–TKI combination therapies, aiming to leverage the potential immunomodulatory effects of VEGFR–TKIs to improve the microenvironment and achieve potent control of rapidly progressing disease.

3. The “SETD2mut + high TMB” model: SETD2 mutations, which induce genomic instability, often lead to an elevated TMB [15, 36, 38]. Clinical evidence indicates that SETD2 mutations are associated with increased response rates and prolonged overall survival following ICI treatment [46]. Thus, these patients are considered potential candidates for superior benefit from ICI therapy, warranting focused attention in clinical practice and further investigation in prospective studies [46].

4. The “All Wild-Type” Model: For patients with wild-type status for SETD2, BAP1, and PBRM1, tumor pathogenesis, progression, and treatment response are likely driven by other unknown drivers (such as TCEB1 mutations) [80]. The biological behavior of these tumors is more heterogeneous, and deeper investigations using multiomics technologies are urgently needed to define their molecular subtypes and explore effective therapeutic targets.

By integrating the mutational status of these key genes, a more predictive molecular subtyping system can be constructed. This will allow for the tailoring of the most rational initial treatment strategy (e.g., ICI monotherapy, VEGFR-TKI monotherapy, or their combination) for patients with advanced renal cell carcinoma, ultimately propelling RCC treatment fully into the era of precision medicine (Table 3).

Table 3.

Potential predictive value of the PBRM1/BAP1/SETD2 mutation status in informing treatment selection

Mutation status	Tumor microenvironment/key features	Predicted response to VEGFR-TKI	Predicted response to ICI	Potential prioritized treatment strategy
PBRM1-mut	Nonimmunogenic phenotype; Attenuated IFN-γ signaling	Potential sensitivity	Potential resistance	VEGFR-TKI-based therapy; ICI combinations to overcome resistance
BAP1-mut	Immunosuppressive (e.g., Treg recruitment via CCR5); highly aggressive	Potential resistance	Potential resistance	Aggressive first-line combo (e.g.VEGFR-TKI + ICI) to control rapid progression & modulate TME
SETD2-mut	High TMB; Genomic instability; Altered immune infiltration	Inconclusive	Potential sensitivity	ICI-based therapy(monotherapy or combination)
All wild-type	Heterogeneous; Driven by other unknown drivers	Inconclusive	Inconclusive	Requires further molecular subtyping; consider standard-of-care

Therapeutic implications and future directions

Direct targeting of epigenetic effects

In ccRCC, directly targeting epigenetic abnormalities has emerged as a promising therapeutic strategy aimed at reversing gene silencing and chromatin dysregulation caused by mutations in epigenetic modifiers such as BAP1, PBRM1, and SETD2 [21]. Histone deacetylase inhibitors (HDACis) function by increasing histone acetylation levels, thereby reactivating the expression of tumor suppressor genes and inducing apoptosis in cancer cells. For example, a novel HDAC inhibitor, N-hydroxy-7-(2-naphthylthio)heptanomide (HNHA), has demonstrated potent antitumor activity in RCC models, effectively suppressing tumor growth both in vitro and in vivo through caspase-dependent and cytochrome c-mediated apoptotic pathways [90]. Additionally, DNA demethylating agents such as 5-aza-2’-deoxycytidine can reverse promoter hypermethylation of tumor suppressor genes such as ADAMTS18 and ASC/TMS1, restoring their expression and consequently inhibiting ccRCC cell proliferation and inducing apoptosis [91–93]. Importantly, PBRM1-deficient tumors have been shown to exhibit heightened sensitivity to such DNMT inhibitors [32]. These direct epigenetic interventions not only offer new avenues for ccRCC treatment but also underscore the potential of epigenetic biomarkers—such as DNA methylation profiles or histone modification status—in personalizing medicine by predicting treatment response and facilitating patient stratification [92]. Despite existing challenges, including tumor heterogeneity and drug specificity, combining epigenetic therapies with immune checkpoint inhibitors or targeted agents represents a critical focus for future research [48].

Use of synthetic lethality relationships

The therapeutic strategy of exploiting synthetic lethality presents a promising avenue for targeting RCC with specific epigenetic modifier mutations, aiming to selectively kill cancer cells on the basis of their unique genetic vulnerabilities while sparing normal tissues. For example, preclinical studies have demonstrated that PBRM1-deficient RCC cells exhibit increased sensitivity to DNA methyltransferase (DNMT) inhibitors. The DNMT inhibitor 5-fluoro-2-deoxycytidine (FdCyd) was shown to selectively inhibit the growth of PBRM1-deficient tumor cells in isogenic models, as these cells displayed an enhanced DNA damage response; this agent also reactivated the proapoptotic factor XAF1, suggesting a synthetic lethal interaction between PBRM1 loss and DNMT inhibition [32]. Furthermore, BAP1 loss confers specific vulnerability to bromodomain and extraterminal (BET) inhibitors. Preclinical evidence indicates that BET inhibitors can effectively suppress the growth of BAP1-deficient RCC cells both in vitro and in vivo, highlighting a potential synthetic lethal partnership that could be therapeutically exploited [94]. Similarly, for SETD2-mutant RCC, a synthetic lethal approach involving a combination of DNA hypomethylating agents (HMAs) and PARP inhibitors (PARPis) has been identified. In vitro and in vivo studies revealed that the combination of the HMA 5-aza-2’-deoxycytidine (DAC) and the PARPi talazoparib synergistically increased cytotoxicity specifically in SETD2-deficient ccRCC cell lines but not in SETD2-proficient lines, indicating a synthetic lethal interaction contingent upon SETD2 loss [48]. The underlying vulnerability is likely rooted in the DNA repair defects caused by SETD2 deficiency [38]. These findings underscore the potential of functional genomics and combination screens to uncover novel synthetic lethal interactions, paving the way for the development of targeted therapies tailored to specific epigenetic deficiencies in RCC.

Combined therapy and future directions

Combination therapy, which integrates epigenetic modulators with established treatment modalities, represents a highly promising and clinically viable strategy to increase therapeutic efficacy in RCC. A key approach involves pairing epigenetic drugs with ICIs. HDACis, such as the novel agent HNHA, can induce apoptosis and alter the tumor cell phenotype, potentially increasing the immunogenicity of the tumor microenvironment and thereby sensitizing tumors to immunotherapy [90]. Furthermore, DNA demethylating agents can reverse the hypermethylation and silencing of tumor suppressor genes [32], an effect that could be harnessed to increase tumor antigen presentation and improve the ICI response [93]. In addition to immunotherapy, synthetic lethal combinations offer another powerful strategy. For example, SETD2-deficient kidney cancer cells show marked sensitivity to the combined inhibition of DNA methylation and PARP, as demonstrated by the synergistic cytotoxicity of DAC and the PARP inhibitor talazoparib in preclinical models [48]. This approach effectively targets the vulnerabilities inherent to SETD2 loss in DNA damage repair.Additionally, targeting the downstream consequences of epigenetic mutations, such as metabolic reprogramming, is a compelling avenue. SETD2 deficiency has been shown to induce a metabolic switch toward enhanced oxidative phosphorylation in ccRCC, identifying a potential therapeutic target for metabolic inhibitors [41]. Similarly, emerging therapies focus on specific vulnerabilities created by other mutations; for example, BAP1 loss renders renal carcinoma cells more sensitive to BET inhibitors, highlighting a potential targeted combination strategy [94].

The future successful clinical translation of these strategies will depend on biomarker-driven patient selection in clinical trials and a deeper understanding of resistance mechanisms through integrated multiomics approaches [95]. Promising therapeutic strategies targeting specific epigenetic deficiencies in ccRCC are summarized below (Table 4).

Table 4.

Promising therapeutic strategies targeting epigenetic abnormalities in ccRCC

Affected gene/pathway	Primary pathogenic mechanism	Potential therapeutic strategy	Representative agents/approaches	Stage of development
PBRM1 loss	Dysregulated chromatin remodeling; DNA damage response vulnerabilities	Synthetic Lethality (DNMT inhibition)	5-Fluoro-2’-deoxycytidine (FdCyd)	Preclinical
BAP1 loss	H2AK119ub accumulation; PR-DUB complex inactivation	Synthetic Lethality (BET inhibition)	BET inhibitors (e.g., JQ1)	Preclinical
SETD2 loss	Genomic instability; DNA repair defects (H3K36me3 loss)	Synthetic Lethality (PARP + DNMT inhibition)	Talazoparib + 5-aza-2’-deoxycytidine (DAC)	Preclinical
General epigenetic dysregulation	Histone hypoacetylation; Tumor suppressor gene silencing	Direct Epigenetic Targeting (HDAC inhibition)	HNHA, Vorinostat	Preclinical toEarly Clinical Trials
General epigenetic dysregulation	DNA hypermethylation; Immune evasion	Direct Epigenetic Targeting (DNMT inhibition) + Immunotherapy	Azacitidine + Immune Checkpoint Inhibitors (ICIs)	Ongoing Clinical Trials
General epigenetic dysregulation	Altered tumor microenvironment; ICI resistance	Epigenetic Priming for Immunotherapy	HDACi or DNMTi + ICIs	Active area of investigation

Summary

The pathogenesis of ccRCC has moved beyond the traditional VHL-HIF axis paradigm [23]. Large-scale genomic studies have revealed a set of key epigenetic modifier genes—PBRM1, SETD2, and BAP1—located on chromosome 3p [96, 97], which are frequently mutated and serve as core molecular determinants driving tumor heterogeneity and clinical outcomes [21, 65]. Mutations in these three genes are often mutually exclusive and define molecular subtypes with distinct pathological features and prognoses: BAP1 mutations are strongly associated with high-grade, aggressive tumors and serve as the most robust molecular indicator of poor survival [8, 37, 56]; PBRM1 mutations tend to define a relatively indolent subtype linked to better prognosis and potential sensitivity to VEGF pathway-targeted therapy [29], although its role is complex and associated with resistance to immunotherapy [31, 45, 82]; and SETD2 mutations, through genomic instability and epigenetic dysregulation, are linked to intermediate-to high-risk disease features and inferior outcomes [37, 40, 42] but may also enhance the response to immune checkpoint inhibitors [46, 68]. Critically, this review underscores that ccRCC is fundamentally a metabolic disease. Beyond defining molecular subtypes and prognosis, mutations in PBRM1, SETD2, and BAP1 drive profound metabolic reprogramming in ccRCC through distinct mechanisms—PBRM1 loss reinforcing HIF-mediated glycolysis, SETD2 inactivation triggering a switch towards oxidative phosphorylation and enhancing nucleotide synthesis, and BAP1 deficiency promoting lipid metabolic dysregulation [14, 15, 58, 64]. These metabolic alterations are not merely bystander effects [98, 99]; they serve as a central link connecting epigenetic defects to aggressive phenotypes, cancer stemness, and an immunosuppressive microenvironment, forming a critical “epigenetic-metabolic-stemness axis“ [39, 62, 83, 84]. This axis provides a solid theoretical foundation for future precision therapeutic strategies that simultaneously target epigenetic vulnerabilities, metabolic dependencies, and stem cell populations.Beyond defining molecular subtypes and prognosis, mutations in PBRM1, SETD2, and BAP1 drive metabolic reprogramming in ccRCC through distinct mechanisms—PBRM1 loss reinforcing HIF-mediated glycolysis, SETD2 inactivation triggering a switch towards oxidative phosphorylation and enhancing nucleotide synthesis, and BAP1 deficiency promoting lipid metabolic dysregulation [14, 15, 58]. These metabolic alterations serve as a central link connecting epigenetic defects to aggressive phenotypes, cancer stemness, and an immunosuppressive microenvironment, providing a solid theoretical foundation for future precision therapeutic strategies targeting the “epigenetic-metabolic axis”.Beyond prognostic stratification, these genes show increasing promise as predictive biomarkers, influencing the tumor response to both immunotherapy and targeted therapies [29, 45, 85]. Future therapeutic strategies are evolving toward composite models that integrate these mutational statuses to enable precise molecular subtyping and risk-adapted treatment. Furthermore, novel approaches, including direct epigenetic interventions (e.g., HDACi, DNMTi) and the exploitation of synthetic lethal relationships (e.g., DNMTi for PBRM1 loss, BETi for BAP1 loss, HMA+PARPi for SETD2 loss), represent promising new directions for precision therapy in ccRCC [32, 48, 90, 94].

Abbreviations

ccRCC

Clear cell renal cell carcinoma

ICI

Immune checkpoint inhibitor

RCC

Renal cell carcinoma

VHL

Von Hippel‒Lindau

HIFs

Hypoxia-inducible factors

TCGA

The Cancer Genome Atlas

PBRM1

Polybromo-1

SETD2

SET domain containing 2

BAP1

BRCA1 associated protein 1

H3K36me3

H3 lysine 36 trimethylation

ICB

Immune checkpoint blockade

ICIs

Immune checkpoint inhibitors

TMB

Tumor mutational burden

PFS

Progression-free survival

HDACis

Histone deacetylase inhibitors

HNHA

N-hydroxy-7-(2-naphthylthio)heptanomide

DNMT

DNA methyltransferase

FdCyd

Fluoro-2-deoxycytidine

BET

Bromodomain and extraterminal

HMAs

Hypomethylating agents

PARP

Poly ADP-ribose polymerase

PARPi

PARP inhibitors

VEGF

Vascular Endothelial Growth Factor

PDGF

Platelet-Derived Growth Factor

SWI/SNF

Switching/sucrose non-fermenting

PBAF

Polybromo-associated BRG1-associated factors

ATP

Adenosine triphosphate

pT stage

Pathological T stage

HIF

Hypoxia-inducible factor

VEGF

Vascular endothelial growth factor

DNMT

DNA methyltransferase

RNA

Ribonucleic acid

LEDGF

Lens epithelium-derived growth factor

cGAS

Cyclic GMP-AMP synthase

H2A

H2AK119ub

PR-DUB

Polycomb repressive deubiquitinas

VEGF-TKIs

Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors

TMB

Umor Mutation Burden

PBRM1

Polybromo 1

CSS

Cancer-specific survival

STAT1

Signal Transducers and Activators of Transcription 1

IFNγ

Interferon Gamma

IRGs

Immune-related genes

CCR5

C-C chemokine receptor 5

Tregs

Regulatory T cells

PD-L1

Programmed cell death ligand 1

TMB

Tumor mutational burden

FOXP3

Forkhead box P3

mTOR

Mammalian target of rapamycin

PFS

Progression-free survival

KDM5C

Lysine Demethylase 5 C

ADAMTS18

ADAM Metallopeptidase with Thrombospondin Type 1 Motif 18

XAF1

Anti-XAF1 rabbit polyclonal antibody

DAC

5-aza-2′-deoxycytidine

FdCyd

5-Fluoro-2′-deoxycytidine

Author contributions

J.B. and X.C.: Conceptualization, Writing – Original Draft Preparation, Literature Review.X.P.:Visualization, Figure Preparation.J.H.and M.S.: Writing – Review & Editing, Data Curation.S.W.:Supervision, Project Administration, Writing – Review & Editing, Funding Acquisition.All authors have read and agreed to the published version of the manuscript.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethical approval and consent to participate

Not applicable. This is a review article and does not report on any original studies with human participants or animals performed by the authors.

Consent to publication

Not applicable.

Competing interests

The authors declare no competing interests.