<p>Chimeric antigen receptor macrophages (CAR-M) are emerging as a next-generation cellular modality for therapies ranging from viral infection to solid tumors, leveraging innate phagocytic and antigen-presenting functions. Here, we compared CAR constructs incorporating intracellular signaling domains (ICDs) derived from CD3ζ, Fc gamma receptor IIa (CD32a), complement receptor 3 (CR3), and Toll-like receptor 4 (TLR4) in THP-1-derived monocytes and macrophages. Using an anti-viral SARS-CoV-2 model as a screening platform, we subsequently validated key findings in an anti-tumor mesothelin (MSLN) model. Results indicated that CAR^CD32a exhibited superior phagocytic capacity compared with CAR^CD3ζ in both monocytes and macrophages. While combining CR3 (CD11b and CD18) and CD32a domains did not enhance phagocytosis, it significantly increased the expression of pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α). The incorporation of TLR4 signaling domain reduced surface CAR expression and phagocytic capacity but markedly increased inflammatory cytokine induction, suggesting that TLR4-driven cytokine production can be enhanced despite diminished phagocytosis in this setting. Furthermore, following phagocytosis, CAR-monocytes induced antigen-specific CD8⁺ T cell activation via antigen presentation. Collectively, these findings highlight CD32a-based and combinatorial ICD designs as a framework for functionally tuned CAR-M platform for solid tumor immunotherapy and anti-viral applications.</p>