Renal cell carcinoma (RCC) is a major global health burden, with an estimated 431,000 new cases and 179,000 deaths reported annually. In Spain alone, approximately 9,200 individuals are diagnosed each year, leading to more than 2,200 deaths. The disease is more common in men than in women, with a male-to-female ratio of about 2:1. Clear cell RCC (ccRCC) is the predominant histological subtype, accounting for nearly 75% of all kidney cancers.
Over the past two decades, treatment outcomes for patients with metastatic RCC have improved dramatically. Survival rates have doubled, and in some cases nearly tripled, owing to the approval of more than 20 treatments that have reshaped the clinical landscape. Current first-line therapeutic strategies rely on a combination of antiangiogenic agents and immune checkpoint inhibitors (Figure 1). Despite these advances, clinical responses remain heterogeneous: while some patients achieve durable disease control, others display intrinsic resistance to therapy or acquire resistance within months of treatment initiation.
Figure 1. Renal cancer treatment evolution and molecular targeting in VHL-mutated tumors. The timeline shows the chronological development of therapeutic approaches for renal cell carcinoma. Early treatments included cytokines (IFN-α, IL-2) followed by the introduction of targeted therapies beginning with antiangiogenic agents (red text) and subsequent mTOR inhibitors (blue text). Immunotherapy agents (green text) were introduced later, starting with nivolumab (2015) and expanding to combination therapies including nivolumab plus ipilimumab (2018) and various antiangiogenic and immunotherapy combinations (2019-2023). The novel HIF2α inhibitors (black text) were approved first for hereditary VHL disease and later for sporadic renal cancer (2021-2023). The central diagram illustrates the molecular landscape of VHL-mutated renal cell carcinoma, highlighting key therapeutic targets: VEGFR pathway (targeted by antiangiogenic drugs), mTORC1 signaling (targeted by mTOR inhibitors), immune checkpoint inhibitors including anti PD1/PDL1 and CTLA4 (targeted by immunotherapy agents), and HIF pathway (targeted by HIF2α inhibitors). The tumor microenvironment shows the complex interplay between cancer cells, immune cells, and vascular components that form the basis for current combination treatment strategies.
The hallmark of ccRCC is the inactivation of the tumor suppressor gene VHL, which drives pseudohypoxia through the accumulation of hypoxia-inducible factor (HIF) α subunits. However, VHL loss alone is insufficient for tumorigenesis, and additional cooperating genetic alterations are required. Notably, more than 60% of ccRCC tumors acquire inactivating mutations in chromatin remodeling genes such as PBRM1, SETD2, BAP1, or KDM5C (Figure 2).
The current therapeutic landscape reflects these biological features: antiangiogenic agents and immune checkpoint inhibitors target two defining characteristics of ccRCC—(i) the extensive tumor angiogenesis resulting from VHL-mediated pseudohypoxia and (ii) the pronounced immune cell infiltration that characterizes this subtype. Despite these advances, patient responses remain highly variable, and the molecular determinants of therapeutic sensitivity or resistance are poorly understood. Furthermore, predictive biomarkers successfully applied in other cancers, such as PD-L1 expression or tumor mutational burden (TMB) for immunotherapy response, have not proven effective in ccRCC. As a result, clinicians currently lack reliable tools to predict which patients will benefit from treatment, limiting the ability to personalize therapy and optimize outcomes
Figure 2. The inactivation of VHL is the driver event of clear cell renal cell carcinoma (ccRCC). A) ccRCC are aggressive tumors characterized by homogeneous inactivation of the tumor suppressor VHL; however, other cooperating events are required for tumor development. The most frequent ones are inactivating mutations in chromatin remodeling genes, which have been associated with different ccRCC prognoses and response to drug treatments, as described by us and other groups. B), The inactivation of VHL leads to an uncontrolled accumulation of hypoxia inducible factors (HIF) 1α and 2α, leading to abnormal angiogenesis, metabolism, and cellular proliferation.
Building on our previous findings (part of them presented in Figure 3), we hypothesize that secondary mutations arising after VHL inactivation play a key role in shaping the tumor microenvironment and influencing therapeutic response. Accordingly, our current research investigates how these secondary alterations modulate both the immune and angiogenic landscapes of ccRCC, ultimately affecting sensitivity to antiangiogenic therapies and immunotherapy. In particular, we focus on mutations in the chromatin remodeler genes PBRM1 and KDM5C, given their high prevalence and potential impact on treatment outcomes.
Figure 3. Genetic alterations and gene expression profiles influence angiogenesis and therapeutic response in clear cell renal cell carcinoma (ccRCC). A) Heatmap showing the expression of 16 angiogenesis-related genes in 93 ccRCC tumors and 8 normal kidney tissue samples, with PBRM1 and KDM5C mutational status indicated in red. B) Response of ccRCC patients to the VEGFR-TKI drug sunitinib (n=343; IMmotion151 clinical trial) according to PBRM1 and KDM5C mutational status, represented as a bar chart. C) Kaplan–Meier curve of progression-free survival (PFS) in patients stratified by PBRM1 and KDM5C mutations. D) PFS of patients with advanced ccRCC treated with the immune checkpoint inhibitor (ICI) atezolizumab plus the antiangiogenic drug bevacizumab, or with sunitinib monotherapy, stratified by PARP1 expression and PBRM1 mutational status. Adapted from Santos et al. 2023 (Am J Cancer Res; PMID: 37293154) and Lanillos et al. 2022 (Eur Urol; PMID: 35688666).