Macrophages have emerged as attractive candidates for cancer immunotherapies due to their ability to engulf and destroy targets through a process called phagocytosis. These specialized cells distinguish between "self" and "foreign" using the CD47-SIRPα axis, a mechanism that cancer cells have unfortunately exploited to evade macrophage immune response. Therapeutic approaches targeting CD47 have shown limited clinical efficacy, raising questions about the reasons behind these failures. One such question is whether a macrophage's CD47 can interact with its own SIRPα (in cis). Through antibody blockade and genetic knockdown, we discovered that inhibiting/depleting macrophage CD47 prior to assay increases phagocytosis. Additional assays revealed decreased CD47 availability on the cell surface for antibody binding when both CD47 and SIRPα are co-expressed, suggesting ongoing cis interactions between the two molecules. These findings highlight an additional consideration when engineering effective macrophages: some basal level of inhibition induced by CD47-SIRPα cis interactions. We then aimed to address an unanswered question in the macrophage research field: How much CD47 inhibition/depletion is necessary to achieve successful therapeutic outcomes? By using mismatch CRISPR-interference to titrate CD47 expression in melanoma, we determined that repressing CD47 expression to a surface density of 11 CD47 molecules/μm2 is required to clear 3D tumoroids and achieve any success in vivo, setting up potential therapeutic benchmarks to explore to improve efficacy of CD47-based therapies. We then briefly delved into the biophysical origins of aneuploidy, the presence of an abnormal number of chromosomes, which appears to be most sustainable in solid tumors. Aneuploidies often confer fitness advantages to cancer cells, which could pose challenges for macrophage-mediated therapies. Much interest surrounding macrophages is due to their ability to penetrate solid tumors, but these same solid tumors could potentially confer evolutionary advantages to cancer cells. However, we find that chromosomal instability, at least in its early stages while cancer cells are still adapting to the aneuploidies, favors macrophage responses against cancer. Our findings from 3D tumoroids and in vivo mouse models demonstrated that chromosomally unstable tumors are effectively cleared under conditions of maximal phagocytosis, in stark contrast to their chromosomally stable counterparts, as long as CD47 is depleted.