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Review
. 2025 Jun 16:17:17588359251345722.
doi: 10.1177/17588359251345722. eCollection 2025.

Recent progress in non-clear cell renal cell carcinoma: biology and therapeutic strategies

Ahmet Yildirim  1 , Marcus W Moses  2 , Margo Gerke  2 , Yash Jani  3 , Jillian C Thompson  2 , Umut Akova  2 , Mehmet A Bilen  4   5
Affiliations
Review

Recent progress in non-clear cell renal cell carcinoma: biology and therapeutic strategies

Ahmet Yildirim et al. Ther Adv Med Oncol. .

Abstract

Non-clear cell renal cell carcinomas (nccRCC) comprise a heterogeneous group of rare malignancies, accounting for approximately 20% of all kidney cancers. Given the rarity of these diverse subsets of RCC, the treatment paradigm for nccRCC is often based on treatment strategies utilized in the management of clear cell renal cell carcinoma (ccRCC), which may not fully address the distinct molecular and genetic drivers unique to nccRCC tumors. However, recent advances in the molecular characterization of nccRCC have led to the identification of new therapeutic targets, resulting in the development of more targeted therapies for nccRCC treatment. Furthermore, the role of molecular characterization of renal tumors is emphasized in the 2022 World Health Organization reclassification of genitourinary tumors, given that delineation of renal tumor subtypes now also relies on genetic markers. In order to highlight this evolving treatment landscape, our review provides a comprehensive summary of recent progress related to the biology and management of nccRCC subtypes.

Keywords: immunotherapy; nccRCC; non-clear cell renal cell carcinoma; papillary RCC; targeted therapy.

Plain language summary

Understanding and treating rare kidney cancers: updates on non-clear cell renal cell carcinomas Non-clear cell renal cell carcinomas are rare types of kidney cancer that account for about 20% of all cases. These cancers are very diverse and often treated like the more common clear cell type, even though their biology and genetics are different. In 2022, the World Health Organization updated the classification of these rare kidney cancers, making it easier to identify specific subtypes and develop targeted treatments. This review highlights recent advancements in understanding biology and explores new treatment strategies that could help patients with these rare kidney tumors.

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Conflict of interest statement

M.A.B. reports personal/consulting fees from and/or service on an advisory board of AstraZeneca, Bayer, Bristol Myers Squibb, Calithera Biosciences, Eisai Inc., EMD Serono, Exelixis Inc., Genomic Health, Janssen, Nektar, Pfizer, SeaGen, and Sanofi; and grants to his institution from AAA, AstraZeneca, Bayer, Bristol Myers Squibb, Genentech/Roche, Genome & Company, Incyte, Merck, Nektar, Peloton Therapeutics, Pfizer, SeaGen, Tricon Pharmaceuticals, and Xencor outside the submitted work. The remaining authors disclosed no conflicts of interest.

Figures

Figure 1.
Figure 1.
A summary of genetic alterations observed in non-clear cell renal cell carcinoma by subtype. Source: Created in BioRender; Gerke (2025) https://BioRender.com/u63w464.
Figure 2.
Figure 2.
Mutations in the SWI/SNF chromatin remodeling complex and their impact on tumor cells. Source: Created in BioRender; Gerke (2025) https://BioRender.com/i18x607.
Figure 3.
Figure 3.
Simplified visualization of NAD+ production pathways. Mutations in the FH gene result in the accumulation of fumarate, leading to global DNA hypermethylation and subsequent silencing of NAPRT. FH-mutant tumor cells rely on the NAD+ salvage pathway for NAD+ production. Inhibiting NAMPT disrupts this pathway and induces tumor cell death. Additionally, PARP inhibitors can be used in combination with NAMPT inhibitors for synergistic tumor cell killing. The five arrows in the de novo synthesis pathway indicate the five additional steps to synthesize quinolinic acid from tryptophan. *PARPs are not the only enzyme that converts NAD+ to NAM; sirtuins also catalyze that transformation. NAMPT, nicotinamide phosphoribosyl transferase.
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