Abstract A005: Biologic insights from spatial analysis of sarcomatoid renal cell carcinoma metastasis to inform therapeutic strategies

Abstract Sarcomatoid renal cell carcinoma (sRCC) is an aggressive trans-differentiation process that can arise in any RCC subtype, most commonly in clear cell RCC (ccRCC). Kidney tumors with sRCC metastasize at high rates (> 50% of cases), and these metastases can have pure ccRCC or sRCC histology, or a mix of the two. Despite the aggressive nature of sRCC, they are more responsive to immune checkpoint inhibition (ICI) in comparison to non-sRCC tumors, prompting the widespread use of ICI-based therapy combinations for metastatic sRCC. However, only approximately half of patients derive meaningful benefit, and the degree that metastatic histology and molecular features shape treatment response are unknown. In this study, we used single cell spatial transcriptomics and proteomics to study 6 matched ccRCC/sRCC primary tumors and metastatic lesions and 1 unmatched metastatic lesion. Two matched primary/metastatic pairs underwent analysis using the Bruker CosMx platform with a 1000-gene single cell transcriptomic panel and 4 matched pairs and 1 single metastasis were profiled using the Singular G4X platform incorporating a 500-plex single cell spatial transcriptomic gene panel and 18-plex proteomic panel. Across all cases, each metastatic lesion demonstrated a dominant tumor cell phenotype, either ccRCC or sRCC, which corresponded with histologic evaluation. Metastases enriched for sRCC features exhibited increased expression of MHC factors, cytokines, and immune checkpoints, as well as increased CD8 T-cell infiltrate and immune cell co-localization, suggesting features of potential responsiveness to ICI. In contrast, metastases enriched for ccRCC showed reduced expression of immune-related pathways and instead demonstrated upregulation of angiogenic programs including VEGFA, suggesting potential increased responsiveness to VEGF-targeted tyrosine kinase inhibitors rather than ICI. All metastatic lesions demonstrated increased immunosuppressive features compared to the matched primary through upregulation of genes known to hinder immune response such as APOE and CCN1. Collectively, these findings expose the heterogeneity of molecular features in sRCC metastases which may critically shape response to systemic therapy. These results support the potential value of biopsy and molecular profiling of metastatic sites to optimize therapeutic decision-making in metastatic sRCC. Citation Format: Hyeyeon Gong, Stephanie The, Kalins Banerjee, Tyler Robinson, Steven Monda, Simpa S. Salami, Evan T. Keller, Allison May. Biologic insights from spatial analysis of sarcomatoid renal cell carcinoma metastasis to inform therapeutic strategies [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Kidney Cancer Research: From Molecular Insights to Therapeutic Breakthroughs; 2026 Mar 13-16; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_2):Abstract nr A005.