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Tumor behavior is intricately dependent on the oncogenic properties of cancer cells and their multi-cellular interactions. To understand these dependencies within the wider microenvironment, we studied over 270,000 single-cell transcriptomes and 100 microdissected whole exomes from 12 patients with kidney tumors, prior to validation using spatial transcriptomics. Tissues were sampled from multiple regions of the tumor core, the tumor-normal interface, normal surrounding tissues, and peripheral blood. We find that the tissue-type location of CD8+ T cell clonotypes largely defines their exhaustion state with intra-tumoral spatial heterogeneity that is not well explained by somatic heterogeneity. De novo mutation calling from single-cell RNA-sequencing data allows us to broadly infer the clonality of stromal cells and lineage-trace myeloid cell development. We report six conserved meta-programs that distinguish tumor cell function, and find an epithelial-mesenchymal transition meta-program highly enriched at the tumor-normal interface that co-localizes with IL1B -expressing macrophages, offering a potential therapeutic target. [Display omitted] • Single-cell and spatial sequencing reveals key features of renal cell carcinoma (RCC) • Intra-tumoral heterogeneity of CD8+ clonotypes dwarfs that from somatic mutations • RCC cells showing epithelial-mesenchymal transition (EMT) enrich at tumor edges • Macrophages expressing IL1B correlate with EMT and could have therapeutic importance Li et al. use single-cell and spatial sequencing to examine the cellular features of kidney tumors and classify cancer cells according to function. They find a more invasive phenotype at the interface separating tumor with normal kidney, which appears to be driven by IL-1β signaling in macrophages. [ABSTRACT FROM AUTHOR]