Myeloid cells, including monocytes and macrophages are the primary orchestrators of immune responses and are found to accumulate abundantly in solid tumors. These cells express a wide range of innate immune sensors such as Toll-like receptors (TLRs), RIG-I and cGAS-STING. The activation of these innate immune pathways can remodel tumor microenvironment and initiate broad immune responses against tumor. Here we designed a new class of chimeric antigen receptors for monocytes that couple tumor recognition with multiple innate immune signaling domains. We screened a broad range of innate immunity signaling molecules and optimized a CAR that incorporates a domain of the TLR adaptor molecule TRIF. The TRIF-CAR targeting human HER2 upregulated the pro-inflammatory cytokines and chemokines including IP10, CCL5 and IFNalpha and enhanced tumor killing activity. Transcriptome-wide analysis revealed that the addition of TRIF to the CAR broadly upregulated genes associated with a pro-inflammatory response, T-cell co-stimulation as well as myeloid cell migration and trafficking. Immunosuppressive molecules such as TREM2 were downregulated. Our data show that the incorporation of a TRIF domain into a myeloid-specific CAR can enhance the innate anti-tumor activity of myeloid cells.