Human tumors are complex ecosystems whose fate is determined by a balance of interactions between cancer cells and the host. Cancer immune evasion is a requisite for the development and maintenance of cancers, and determines response or resistance to modern immunotherapies. Emerging technologies enable more precise, scalable, and refined interrogation of these complex, poorly understood interactions and pave the way toward improved therapies. Informed by multi-modal single-cell profiling of human tumors and analysis of population genetics, we employ functional screens to mechanistically define and tune genomic (e.g., chromosomal instability), adaptive (e.g., CD58-CD2 axis) and microenvironmental features (e.g., T cell states) impacting tumor immunity.