Cancer immunotherapy by blocking immune inhibitory checkpoints or engineering T cells has revolutionized cancer treatment for many patients, however, for the majority of patients with advanced solid cancers sustained clinical benefit is not experienced. Access and survival/function in the tumor microenvironment are major barriers for T cell-based therapies. Unlike T cells, myeloid cells are found to readily accumulate in tumors, in some cases contributing up to 50% of the tumor mass. Furthermore, only cells of the myeloid lineage are capable of phagocytosis, liberating and presenting neoantigen, subsequently recruiting and activating the numerous arms of the adaptive immune response. Irrespective of this potential genetic modification of myeloid cells to harness these activates has not been addressed. To overcome these barriers the Activate, Target, Attack & Kill (ATAKTM) myeloid cell platform has been developed. Inspired by inflammatory innate immune receptors capable of triggering immune activation, chimeric antigen receptors with a HER2 or CD5 cancer recognition domain were designed to include a combination of innate immune intracellular domains derived from a number of innate immune receptors including Fcg, Fca, Fce, CD40, NLRP3 (PYD domain), PI3K, TNFRI, TNFRII, MYD88, STING, MSR1, MERTK, SIRPa switch domains, RIGI/MDA5 (CARD domain). These engineering receptors were subsequently expressed in THP-1 cells (ATAK-THP cells). When incubated with antigen ATAK-THP1-cells showed antigen specific phagocytic and cytokine production activity. Subsequent experiments tested HER2-Fcg-PI3K or CD5- Fcg-PI3K expression in primary CD14+ monocytes isolated from healthy donor leukopacs. These cells also showed antigen specific activity. Importantly, the CD5- ATAK myeloid cells were observed to have significant activity against a human T cell lymphoma in a NSG mouse model. In conclusion the data show that primary myeloid cells engineered with innate immune inspired CAR’s can be generated and engineered to kill human cancers. In vitro and in vivo studies show promising pre-clinical acticty supporting further clinical development.