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Abstract Background Immunotherapy has improved survival for patients with advanced clear cell renal cell carcinoma (ccRCC), but resistance to therapy develops in most patients. We use cellular-resolution spatial transcriptomics in patients with immunotherapy naïve and exposed primary ccRCC tumors to better understand immunotherapy resistance. Results Spatial molecular imaging of tumor and adjacent stroma samples from 21 tumors suggests that viable tumors following immunotherapy harbor more stromal CD8 + T cells and neutrophils than immunotherapy naïve tumors. YES1 is significantly upregulated in immunotherapy exposed tumor cells. Spatial GSEA shows that the epithelial-mesenchymal transition pathway is spatially enriched and the associated ligand-receptor transcript pair COL4A1-ITGAV has significantly higher autocorrelation in the stroma after exposure to immunotherapy. More integrin αV + cells are observed in immunotherapy exposed stroma on multiplex immunofluorescence validation. Compared to other cancers in TCGA, ccRCC tumors have the highest expression of both COL4A1 and ITGAV. Assessing bulk RNA expression and proteomic correlates in CPTAC databases reveals that collagen IV protein is more abundant in advanced stages of disease. Conclusions Spatial transcriptomics of samples of 3 patient cohorts with cRCC tumors indicates that COL4A1 and ITGAV are more autocorrelated in immunotherapy-exposed stroma compared to immunotherapy-naïve tumors, with high expression among fibroblasts, tumor cells, and endothelium. Further research is needed to understand changes in the ccRCC tumor immune microenvironment and explore potential therapeutic role of integrin after immunotherapy treatment.