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Issue 344: Complex genetic changes drive the emergence of diverse tumor cell populations, making tumor heterogeneity a fundamental feature of cancer. Yet, how genetic alterations interact to reprogram tumor cells and their microenvironment remains largely unknown. Here, the authors develop CHOCOLAT-G2P (C-G2P) a scalable experimental framework that cohesively combines multiplex in vivo functional genomics with spatial transcriptomics. In a proof-of-concept, they generate a tumor-mosaicism mouse model based on a powerset combination of 8 alterations that are introduced in the native context of murine liver, testing 256 genotypes in a single experiment. Capturing 324 annotated tumors across six ~6x6 mm2 sections, C-G2P charted phenotypic landscapes of tumor ecosystems, revealing zonation-associated liver cancer subclasses and connections between tumor subtypes and stromal- as well as immune-cell signatures. Further, C-G2P decoded epistatic relations within compound genotypes relevant to cholangiocarcinoma. C-G2P lays a foundation to systematically decipher complex genetic underpinnings of disease phenotypes within tissue context.