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

ABSTRACT 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. SIGNIFICANCE Single-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.