Mapping Heterogeneity in the Tumor Microenvironment of Renal Cell Carcinoma Through Single-Cell Omics

Renal cell carcinoma (RCC) arises in a highly complex tumor microenvironment (TME), where malignant epithelial cells often make up only a minority of the cancer tissue. Traditional bulk sequencing approaches have provided important insights into RCC biology, but they lack the resolution required to capture the cellular heterogeneity and intricate interactions that shape treatment response. The advancement of single-cell and spatial technologies now allows for the collection and analysis of thousands of cells simultaneously at true single-cell resolution, revealing layers of cellular, regulatory, and spatial complexity that were previously obscured.

A central theme of our review is the evolving understanding of CD8⁺ T-cell exhaustion. Rather than existing as a simple binary state, exhaustion emerges as a dynamic and complex process that is partly governed by epigenetic mechanisms. Single-cell approaches have defined diverse CD8⁺ T-cell subsets and distinct exhaustion trajectories, offering a clearer framework for why certain antitumor immune responses fail and how these specific cellular states may be therapeutically reinvigorated.

We also revisit the traditional binary view of myeloid biology. Tumor-associated macrophages (TAMs) in RCC are highly heterogeneous in phenotype, and single-cell analyses now show that they can be clustered far beyond the simplistic pro- or anti-inflammatory M1/M2 categories. Recognizing this myeloid diversity is important, as the composition of the TME is directly associated with treatment response; immune-enriched TMEs tend to align with therapy response, while stroma-enriched TMEs are linked to resistance.

Cancer-associated fibroblasts (CAFs) represent another key component of the RCC TME. These cells are not only derived from normal fibroblasts but can also originate from multiple cell types within the tissue. They exhibit broad heterogeneity in their transcriptional profiles and play a multifaceted role in shaping the tumor architecture and stromal landscape, further highlighting the complexity of RCC biology.

Finally, the review underscores how single-cell technologies, including scRNA-seq, snRNA-seq, scATAC-seq, T-cell receptor sequencing, and imaging mass cytometry, are collectively transforming our ability to unravel the cellular heterogeneity of RCC. By generating high-resolution maps of immune and stromal cell states, these methods provide a foundation for identifying biomarkers of response and guiding precision immunotherapy strategies. The review also critically analyzes and consolidates the spectrum of transcriptional and phenotypic signatures used to define major TME populations, providing a clearer reference point for researchers and helping standardize how these cell states are interpreted across RCC studies.

Readers are invited to explore the full review to see how these single-cell insights are reshaping our understanding of RCC and advancing the path toward more precise, personalized immunotherapy approaches.

Written by: Betul Gok Yavuz,^1,3 Narmina Khanmammadova,^2,3 Zuhair Majeed,³ Mostafa I.H. Ali,³ Merve Hasanov,³ Mehmet Asim Bilen,⁴ Eric A. Singer,⁵ Elshad Hasanov³

Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL
Department of Urology, University of California, Irvine, CA
Division of Medical Oncology, Department of Internal Medicine, Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH
Division of Medical Oncology, Department of Internal Medicine, Emory University, Atlanta, GA
Division of Urologic Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH

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