Spatial and single-cell transcriptomics identify a CD276-rich vascular matrix-associated CAF state linked to adverse outcomes under targeted therapy–immunotherapy combinations in clear cell renal cell carcinoma
Year: 2026
Type: article
Abstract: Background Targeted therapy–immunotherapy combinations have improved treatment outcomes in advanced clear cell renal cell carcinoma (ccRCC), but primary non-response and post-treatment residual progression remain common. Cancer-associated fibroblasts (CAFs) exhibit marked heterogeneity and are closely associated with tumor treatment tolerance; however, specific stromal states associated with treatment non-response, post-treatment residual disease, and immune exclusion remain insufficiently characterized. Methods This study integrated ccRCC single-cell RNA sequencing, bulk transcriptomic cohorts annotated with clinical outcomes, CosMx and Visium spatial transcriptomic data, and multiplex immunofluorescence results. We re-clustered stromal cells to define vascular matrix-associated CAF (vMat-CAF) and construct the corresponding signature, followed by survival, treatment-response, correlation, pseudotime, CellChat, NicheNet, and spatial neighborhood analyses. Results We identified a vascular matrix-associated CAF (vMat-CAF) state in the single-cell stromal atlas of ccRCC, characterized by CD276 enrichment and perivascular localization. Single-cell transcriptomic analysis showed that vMat-CAF was enriched in tumor tissues and relatively enriched in non-responders; bulk clinical cohorts further showed that it was associated with adverse outcomes under targeted therapy–immunotherapy combinations. Further analyses suggested that predicted vMat-CAF-derived LAMA4/COL4A1–CD44 communication was associated with tumor EMT-like programs; meanwhile, vMat-CAF exhibited high CD276 expression, and the association between CD276 and adverse clinical outcomes was more evident in the vMat-CAF-high context. Moreover, spatial transcriptomics and immunofluorescence showed that CD276-high vMat-CAF was enriched in perivascular regions and was associated with a spatial distribution pattern characterized by insufficient infiltration of CD8 + T cells into the tumor center. Conclusions vMat-CAF is a CD276-enriched perivascular stromal state associated with adverse outcomes under targeted therapy–immunotherapy combinations in ccRCC. Further analyses connected this state with tumor EMT-like programs, the context-dependent clinical significance of CD276, and restricted CD8 + T-cell infiltration into the tumor center, supporting a candidate perivascular stromal–immune gating model.
Source: Frontiers in Immunology
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,801
OpenAlex ID: W7225784120