Background For the majority of patients with advanced solid tumors, sustained clinical benefit with immunotherapy has yet to be achieved. Myeloid cells, including monocytes and macrophages are the primary orchestrators of immune responses and are found to accumulate in tumors, in some cases contributing up to 75% of the tumor mass. Myeloid cells express a wide range of innate immune sensors such as Toll-like receptors, RIG-I and cGAS-STING as well as co-stimuulatory molecules like CD40. The activation of these innate immune pathways in myeloid cells can be associated with anti-tumor immune response. Notwithstanding the ability of the myeloid cells to infiltrate tumors and elicit broad immune responses, technologies capable of harnessing these cells to target cancer remains elusive.

Methods Here we designed and engineered a new class of chimeric antigen receptors that couple tumor recognition with multiple innate immune signal domains, referred to as Activate, Target, Attack & Kill (ATAK^TM) receptors. By combining cancer recognition domains with intracellular signaling domains from innate immune receptors such as Fcg, TLR and cytokine receptors, we show that myeloid cells can be controlled and programmed to recognize cancer and elicit a broad and tunable immune response. Critically, in mice with established, highly immunosuppresive B16 melanoma tumors, delivery of monocytes engineered to express ATAK receptors results in anti-tumor activity. Our data show the versatility of building ATAK receptors by harnessing innate immune pathways and support their clinical development in cell therapies.