a, A schematic of copy number alteration frequency in tumors, which guides the selection of target regions to engineer in cellular models via MACHETE. b, Chromosome 9p21.3 (syntenic to mouse 4C4) coordinates cell intrinsic and extrinsic tumor suppression. MACHETE engineering of the two most common configurations of 9p21.3 loss (ΔL and ΔS) identified the contribution of tumor-derived type I IFNs in promoting immune surveillance and metastasis suppression. c, MACHETE can dissect the contribution of large cis-regulatory elements to gene regulation. d, Potential application of MACHETE to elucidate genome structure/architecture via the functional interrogation of topological associated domains (TADs). e, MACHETE-aided integration of reporters into a locus of interest. Using the strong positive/negative selection and CRISPR-mediated excision of the MACHETE cassette can aid in the integration of reporters (e.g., fluorescent proteins, recombinases, etc.) to loci that are poorly expressed.