42 Spatial Mapping of the Sarcomatoid Transition in Chromophobe Renal Cell Carcinoma Reveals a Reprogrammed Tumor-Immune Interactome

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Abstract Background Chromophobe Renal Cell Carcinoma (ChRCC), derived from the intercalated cells of the collecting duct, typically follows an indolent clinical course. However, approximately 5–8% of cases undergo sarcomatoid transformation (sChRCC), a high-grade dedifferentiation resulting in a spindle-cell morphology and a rapid, metastatic trajectory. This transition represents a profound clinical shift; while classic ChRCC (cChRCC) is often surgical, sChRCC is notoriously refractory to anti-angiogenic agents and tyrosine kinase inhibitors (TKIs). The molecular drivers and spatial architecture of this transition have remained elusive due to the rarity of the subtype and the limitations of bulk genomic approaches that mask the spatial crosstalk between malignant cells and the surrounding stroma. Methods We established a high-resolution spatial transcriptomic atlas of ChRCC using the Xenium 5K platform, profiling n = 6classic and n = 3 sarcomatoid tumor samples. We integrated this subcellular spatial data with bulk RNA-seq and validated findings through immunohistochemistry (IHC) for markers such as CD8, CD68, and CD163. Using reference-based mapping and intercellular communication analysis, we dissected the “niche-specific” interactions that define the sarcomatoid tumor microenvironment (TME). Results Our spatial atlas revealed a profound cellular reorganization during the sarcomatoid transition. Compositional analysis showed that while cChRCC is predominantly “immune-excluded,” sChRCC displays a massive enrichment of T cells and macrophages deeply infiltrated within mesenchymal bundles. We identified that sChRCC tumor cells undergo coordinated mesenchymal reprogramming, driven by a robust Epithelial-Mesenchymal Transition (EMT) signature (e.g., ADAM12, POSTN, COL5A1) and a distinct dysregulation of ferroptosis-related metabolic pathways. We observed a paradoxical “infiltration-exhaustion” state: despite high T-cell density, these cells exist in an advanced state of exhaustion, expressing high levels of CTLA4, TIGIT, LAG3, and HAVCR2. Spatial mapping confirmed the co-localization of these receptors with the inhibitory ligand CD276 (B7-H3) on sarcomatoid tumor cells and cancer-associated fibroblasts (CAFs), suggesting a dominant spatial mechanism of immune evasion. Intercellular communication analysis nominated the CXCL12-CXCR4 axis as a primary “spatial sculptor.” While cChRCC signaling is sparse and focused on vascular integrity (VEGFA-VEGFR2), sChRCC is characterized by a dense, complex network where tumor cells and CAFs serve as central signaling hubs. We identified a unique CXCL12 gradient derived from tumor cells that acts as a chemoattractant for T cells and M2-polarized macrophages (CD163+, MRC1+). Furthermore, a novel plasma cell-to-tumor signaling hub via the GAS6-AXL axis was identified as a driver of EMT progression. Physical remodeling was evidenced by a massive increase in collagen-integrin signaling (e.g., COL1A1-CD44), which effectively “traps” the immune infiltrate within a pro-tumorigenic fibrotic niche. Conclusions This study provides the first definitive structural blueprint of the sChRCC microenvironment. We demonstrate that the sarcomatoid transition is not merely a cell-intrinsic morphological shift, but a wholesale reorganization of the tumor ecosystem into a highly coordinated, immunosuppressive niche. By mapping these “Achilles’ heels,” we move beyond simple genomic mutations to nominate B7-H3, the CXCL12-CXCR4 axis, and AXL signaling as spatially localized therapeutic vulnerabilities. These findings suggest that future clinical efforts for sChRCC must pivot from traditional anti-angiogenic strategies toward multi-modal immunotherapies that simultaneously disrupt mesenchymal reprogramming, inhibit suppressive myeloid recruitment, and reinvigorate the sequestered, exhausted T-cell population. This spatial framework offers a biologically informed path toward personalized treatment for this lethal ChRCC variant.