Editor’s Note: Non–clear cell renal cell carcinoma (nccRCC) remains one of the most challenging areas in kidney cancer owing to its marked heterogeneity, low incidence, and complexity in diagnosis and treatment. Conventional therapeutic strategies have largely been extrapolated from clear cell renal cell carcinoma (ccRCC), yet their effectiveness has reached a plateau, offering limited survival benefit to patients.
In this interview, Professor Hao Zeng provides a comprehensive overview of his team’s translational efforts in nccRCC, spanning the entire continuum from diagnosis to treatment. By integrating artificial intelligence with molecular pathology, the team has advanced precision diagnostics; through multidisciplinary collaboration (MDT), they have redefined the role of surgery and local therapies; and by leveraging molecular subtyping, they have developed targeted–immunotherapy combination strategies for specific subtypes such as FH-deficient renal cell carcinoma. These initiatives have successfully transformed clinical challenges into research directions, resulting in meaningful survival improvements, with median overall survival (OS) approaching 60 months.
Importantly, Professor Zeng highlights key future priorities: the profound heterogeneity of nccRCC necessitates individualized molecular characterization, while the lag in novel target discovery and drug development remains a critical barrier to achieving true precision medicine. This interview offers valuable guidance for clinicians managing nccRCC and provides important insights into the future of precision therapy in renal cancer.
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Oncology Frontier – UroStream
Your team has focused on non–clear cell renal cell carcinoma (nccRCC) for many years and has conducted a series of diagnostic and therapeutic explorations. Could you introduce the main research directions of your team and the key achievements to date?
Professor Hao Zeng:
Our team has been dedicated to clinical and translational research in non–clear cell renal cell carcinoma since 2017. All of our work is driven by unmet clinical needs and can be broadly categorized into four major areas.
First, improving the accuracy of preoperative diagnosis.
Preoperative identification of nccRCC remains challenging, and in most cases the pathological subtype can only be confirmed after surgery. Our primary focus has been on optimizing and innovating imaging techniques to predict potential nccRCC subtypes before surgery. This information is critical for guiding surgical decision-making, including the choice between partial and radical nephrectomy, determining the extent of resection, and assessing the need for lymph node dissection. This line of research is technically demanding, and we are currently pursuing stepwise breakthroughs, beginning with individual subtypes.
Second, achieving standardized and precise pathological diagnosis.
Because of the relatively low incidence of nccRCC, diagnostic experience in pathology is often limited. In close collaboration with our pathology colleagues, we have conducted in-depth studies in conventional histopathology, molecular pathology, genomic testing, and AI-assisted diagnostic approaches. For example, in FH-deficient renal cell carcinoma, the diagnostic accuracy of conventional pathology is approximately 70%. By introducing novel molecular markers and developing AI-based diagnostic models, we have increased diagnostic accuracy to over 95%, thereby establishing a solid foundation for subsequent precision treatment.
Third, redefining and strengthening the value of surgical treatment.
Through translational research and large-scale clinical practice, we have systematically evaluated the role of surgery in nccRCC, including cytoreductive nephrectomy (CN), resection of resectable metastatic lesions, and local treatment of unresectable metastases. Our data indicate that nccRCC patients who undergo treatment of both the primary tumor and metastatic sites can achieve a median OS approaching 60 months. This level of survival benefit is comparable to, and in some cases even exceeds, that observed in patients with clear cell renal cell carcinoma.
Fourth, exploring precision systemic treatment strategies.
At present, most systemic therapies for nccRCC are adapted from treatment regimens developed for ccRCC, and their efficacy remains limited. Based on distinct driver genes and pathological subtypes, we have initiated a series of clinical studies. The first major breakthrough was achieved in FH-deficient renal cell carcinoma. This subtype is characterized as an immunologically “hot” tumor. Using a targeted–immunotherapy combination of axitinib and PD-1 inhibitors, the median OS of patients with metastatic disease increased from less than 13 months to more than 40 months, while median progression-free survival (PFS) improved from under 8 months to nearly 20 months. Moving forward, we will continue multicenter collaborations across China to define precise treatment strategies for additional nccRCC subtypes.
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Oncology Frontier – UroStream
In the era of rapidly advancing targeted therapy and immunotherapy, how do you view the role and value of cytoreductive nephrectomy (CN) in patients with metastatic nccRCC? What standardized approaches does your team use for patient selection and perioperative management?
Professor Hao Zeng:
This is an excellent and highly relevant question. Despite meaningful progress in systemic therapies, their real-world effectiveness remains clearly limited. For most patients, disease progression still occurs after approximately two years. In the absence of more effective systemic options, the importance of local treatment becomes particularly pronounced.
The primary objectives of cytoreductive nephrectomy are to reduce overall tumor burden, eliminate factors within the primary tumor that may compromise the efficacy of systemic therapy, and alleviate local symptoms. This fundamental principle has remained consistent across treatment eras, from cytokine-based therapy to the current era of combined targeted and immunotherapy. For nccRCC—where systemic treatment outcomes generally lag behind those of clear cell carcinoma—enhancing local treatment is especially critical.
In addition, patients with nccRCC tend to be younger, with a median age at diagnosis of approximately 40 years. They often have strong motivation for treatment and relatively good physical condition, enabling them to tolerate more aggressive therapeutic strategies.
With regard to patient selection and management, our team develops individualized strategies based on the biological behavior of specific nccRCC subtypes. For indolent, low-risk subtypes, surgical strategies may be relatively conservative. In contrast, for highly aggressive tumors with potentially resectable disease, we actively engage in multidisciplinary collaboration (MDT) involving pathology, radiology, nuclear medicine, and other specialties. Advanced imaging modalities are used to comprehensively evaluate resectable lesions, after which the most appropriate approach is selected—whether surgery, radiotherapy, or minimally invasive local treatments such as cryoablation or radiofrequency ablation.
At the same time, we integrate genomic testing and transcriptomic analyses to formulate comprehensive, individualized treatment plans aimed at maximizing clinical benefit for each patient.
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Oncology Frontier – UroStream
Finally, beyond the directions already discussed, what other areas do you believe warrant further exploration in the field of nccRCC?
Professor Hao Zeng:
Using FH-deficient renal cell carcinoma or TFE3-rearranged renal cell carcinoma as examples, we can clearly appreciate the extreme complexity of non–clear cell renal cell carcinoma. This complexity is reflected in its pathological features, molecular mechanisms, and multiple other dimensions, and it distinguishes nccRCC fundamentally from the more common clear cell subtype.
At our center, we have actively conducted molecular subtyping of FH-deficient renal cell carcinoma. Using advanced analytical approaches, we have identified at least three distinct molecular subtypes, each characterized by markedly different gene expression patterns, protein profiles, and biological behaviors. Notably, although FH-deficient RCC is generally considered an immunologically “hot” tumor with presumed sensitivity to immunotherapy, our subtyping unexpectedly revealed the presence of an immune “desert” subtype, characterized by minimal immune cell infiltration and a profoundly suppressed immune microenvironment.
Accordingly, the foremost future research priority is individualized precision characterization—that is, tailoring therapeutic strategies based on the unique molecular features of each patient. Given the substantial interpatient heterogeneity in nccRCC, only through such individualized analysis can we deliver the most appropriate and effective treatments.
A second critical direction is drug development driven by novel molecular discoveries. As molecular subtyping continues to advance, new therapeutic targets, distinctive omics signatures, and unique molecular features are likely to emerge. However, many of these currently lack corresponding targeted agents. As a result, even when a patient’s molecular characteristics are clearly defined, effective treatment options may remain unavailable.
Future progress will require substantially increased investment in drug development, including funding, personnel, and infrastructure. Only by aligning precise molecular classification with the availability of matched therapeutic agents can we achieve true precision medicine. This represents a key pathway to improving outcomes for patients with non–clear cell renal cell carcinoma.
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Professor Hao Zeng
