Hasanov, E. | bioRxiv Science

bioRxiv2026

Single-Cell Atlas of Renal Cell Carcinoma Brain Metastasis Uncovers Mechanisms of Immune Dysfunction and Resistance

Brain metastasis (BM) in renal cell carcinoma (RCC) remains poorly understood and often resistant to immune checkpoint inhibitors. We generated a large single-nucleus RNA-seq data of RCC BM, profiling 14 BM samples alongside matched extracranial metastases and primary tumors. Tumor cells in BM displayed neuronal infiltration, neural-like adaptation, and marked remodeling of the microenvironment, including expansion of immunosuppressive myeloid cells and depletion of antigen-presenting dendritic cells. Tumor, immune, and stromal cells exhibited metabolic rewiring characterized by fatty-acid metabolism, oxidative phosphorylation, and MYC-driven programs. CD8 T cells showed terminal exhaustion and impaired proliferative capacity, and tertiary lymphoid structures were absent. Spatial profiling of 12 BM samples (13,128 cells) validated key cellular interactions, while ligand-receptor analysis revealed immunoregulatory circuits between tumor, stromal, and immune cells. These findings define BM-specific adaptations that promote immune evasion and resistance, revealing therapeutic vulnerabilities in RCC BM. SIGNIFICANCESingle-nucleus RNA-sequencing profiling reveals tumor, immune, and metabolic adaptations in renal cell carcinoma (RCC) brain metastases, including neuroglial remodelling and immunosuppressive niche formation. These findings identify immune evasion mechanisms that could contribute to therapeutic resistance, providing new avenues for site-specific therapeutic interventions to improve treatment efficacy and outcomes in patients with RCC BM.

cancer biology↗

bioRxiv2026

Deciphering the Genomic Landscape of Renal Cell Carcinoma Brain Metastases

Brain metastases from renal cell carcinoma (RCC) remain a major cause of morbidity and mortality, yet the genomic features associated with metastatic dissemination remain poorly understood. Whole-exome sequencing was performed on 72 RCC brain metastasis samples with matched normal. To identify candidate genomic alterations associated with brain metastasis, the genomic alterations detected in the brain metastases were compared against alterations in extracranial metastases from the MSK-ECM cohort (n=137) and primary RCC tumors from TCGA (n=432) by case-control analyses. Candidate alterations were also identified through matched-pair analyses comparing brain metastases with matched primary tumors or extracranial metastases from the same patient (n=25). A random survival forest model incorporating the candidate CNA events was developed to predict overall survival. The candidate CNAs were further evaluated using functional experimental data from MetMap and DepMap. Survival analyses were conducted to assess the prognostic relevance of these alterations. We identified recurrent CNAs enriched in RCC brain metastases, including 4q loss, 7p gain, 7q gain, 8p loss, 8q gain, 9p21.3 deletion, 12q15 amplification, and 14q loss. These alterations were associated with significantly poorer patient survival among RCC patients. A random survival forest model based on these CNA events stratified TCGA-KIRC patients into prognostically distinct risk groups (C-index = 0.64). Among the recurrent CNAs, 8p loss, 8q gain, 9p21.3 deletion were associated with increased incidence of brain metastases across multiple primary cancer types in xenograft mouse models. These alterations were also strongly associated with metastatic progression and poor prognosis across RCC, lung adenocarcinoma, breast cancer, and melanoma. These findings indicate a shared genomic basis for brain tropism and highlight the potential utility of copy-number alterations as biomarkers for risk stratification and clinical decision-making.

genetics↗