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Editorial: Unraveling renal cell carcinoma: pathogenesis; therapeutic strategies; and future perspectives
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DOI：10.3389/fmed.2026.1946789.png)
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Abstract
En 中文
Renal cell carcinoma (RCC) is a highly heterogeneous group of malignant tumors; with distinct differences among its subtypes in terms of molecular characteristics; biological behavior; and clinical response to treatment. Recently; the continuous development of anti-angiogenic agents; immune checkpoint inhibitors; and combination therapy strategies has significantly improved clinical outcomes for some patients. However; there are marked differences in treatment response among patients; and drug resistance and disease recurrence remain major factors limiting long-term benefits. Therefore; identifying key factors influencing tumor progression and treatment response is crucial for establishing more precise risk stratification and treatment strategies. The studies included in this special issue explore RCC from multiple perspectives; including molecular mechanisms; microenvironment regulation; precision diagnostics; and treatment optimization; further expanding our understanding of the pathogenesis; progression; and clinical management of RCC. As immunotherapy has entered clinical practice for RCC; the important role of the tumor microenvironment has gradually garnered attention [4]. Metabolic changes in tumor cells not only affect their own survival but can also alter treatment responses by modulating the function of immune cells [5]. Hong et al. developed a prognostic assessment model combining ERO1A expression and the level of CD163⁺ tumorassociated macrophage infiltration; which improved the prediction of postoperative survival compared to traditional TNM staging. This study suggests that metabolicrelated molecular characteristics and the status of immune cell infiltration may jointly influence the prognosis of RCC patients. Furthermore; Pantano et al. analyzed patients with bone-metastatic RCC treated with nivolumab and found that combination therapy with bone-targeted agents; particularly denosumab; was associated with better survival outcomes. Although this study cannot yet prove that bone-targeted therapy directly enhances the efficacy of immunotherapy; the results indicate that the bone microenvironment may play a role in modulating sensitivity to immunotherapy.The highly heterogeneous characteristics of RCC also complicates clinical diagnosis and treatment decision-making [6]. Therefore; accurately determining the tumor's characteristics; grade; and risk of invasion is key to achieving precision therapy. ccRCC is primarily driven by VHL deficiency and abnormalities in the HIF pathway. HIF-2α; as a key regulatory factor that becomes abnormally activated following VHL deficiency; plays a role in regulating angiogenesis; metabolic adaptation; and tumor cell survival; and is considered an important therapeutic target for ccRCC [7]. Yang et al.reported that the HIF-2α inhibitor belzutifan demonstrated good efficacy and safety in patients with advanced ccRCC and suggested that the use of combination therapies warrants further exploration. Chen et al. further noted that monotherapy with HIF-2α inhibitors may be limited by primary or acquired resistance; and that exploring combination therapy strategies is an important direction for future research. Overall; these studies included in this special issue collectively demonstrate a significant shift currently underway in the field of RCC research: a gradual transition from a focus on single driver gene abnormalities to a comprehensive precision medicine model that integrates genetic background; metabolic status; the immune landscape; imaging features; and treatment response. The key to future RCC research lies not only in discovering new therapeutic targets but also in elucidating how different biological characteristics collectively influence patient prognosis and treatment sensitivity. With advancements in multi-omics technologies; AI-assisted diagnosis; and novel combination therapy strategies; precision management of RCC is expected to further enhance patient outcomes. However; some current studies are still primarily based on retrospective analyses; small sample cohorts; or single-center data. Their clinical applicability requires further validation through larger-scale; multicenter; prospective studies. By integrating findings from basic research with the needs of clinical practice; it is anticipated that a more precise; dynamic; and personalized RCC management system will be established in the future.
Keywords:
renal cell carcinoma
immune microenvironment
precision medicine
clear cell renal cell carcinoma
HIF-2α inhibitor
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