Engineering macrophages for effective and safe targeting of CD47 cancer cells in the tumor microenvironment

Tumor-associated macrophages are key myeloid cells in the tumor microenvironment (TME), acting as essential orchestrators of innate and adaptive immune responses. The efficacy of current antitumoral treatments can be promoted by macrophages, thanks to their phagocytosis, tumoricidal activity, and eliciting of adaptive immunity; or restricted by their expression of inhibitory counter-receptors (such as programmed death-ligand 1 or signal regulatory protein alpha). Furthermore, the continuous recruitment of these myelomonocytic cells into tumor tissues makes them attractive candidates for cell therapy with the development of chimeric antigen receptor (CAR) effector cells. This evidence highlights the strong therapeutic potential of macrophage engineering for the treatment of solid tumors. In this line of research, Du et al developed pArg1-CD47 CAR-M φ based on intrinsic Arg1 promoter responsiveness for TME-specific activation of cytotoxicity, effectively overcoming SIRPα inhibition against CD47+cancer cells. In preclinical murine models of breast and gastric cancer, this macrophage cell therapy demonstrated significant regression of established tumors with minimal toxicity towards erythrocytes. Although translating this work from mice to humans remains a significant challenge, it provides hope for the design of myeloid cell therapies with antitumoral efficacy and safe profile for solid tumors.