LAUSR

Simple Summary Immunotherapies offer broad potential to treat many diseases, including cancer. Macrophages are highly abundant immune cells, but are generally inhibited from eliminating tumor cells by ‘self’ signaling. Blocking this macrophage signaling checkpoint with antibodies has gone through clinical trials, which show that efficacy remains elusive especially for solid tumors. Here we show that CRISPR-based deletion of this inhibitory checkpoint is also insufficient to suppress solid metastatic tumors unless combined with a pro-phagocytic tumor-opsonizing antibody. Our tumor model is immunocompetent and resistant to T cell checkpoint blockade, which are typical characteristics of human cancer. We further demonstrate an equally effective cell therapy with antibody-engineered macrophages, and the approach also suppresses model metastatic human tumors. Abstract The macrophage checkpoint interaction CD47-SIRPα is an emerging target for cancer therapy, but clinical trials of monoclonal anti-CD47 show efficacy only in liquid tumors when combined with tumor-opsonizing IgG. Here, in challenging metastatic solid tumors, CD47 deletion shows no effect on tumor growth unless combined with otherwise ineffective tumor-opsonization, and we likewise show wild-type metastases are suppressed by SIRPα-blocked macrophages plus tumor-opsonization. Lung tumor nodules of syngeneic B16F10 melanoma cells with CD47 deletion show opsonization drives macrophage phagocytosis of B16F10s, consistent with growth versus phagocytosis calculus for exponential suppression of cancer. Wild-type CD47 levels on metastases in lungs of immunocompetent mice and on human metastases in livers of immunodeficient mice show that systemic injection of antibody-engineered macrophages also suppresses growth. Such in vivo functionality can be modulated by particle pre-loading of the macrophages. Thus, even though CD47-SIRPα disruption and tumor-opsonizing IgG are separately ineffective against established metastatic solid tumors, their combination in molecular and cellular therapies prolongs survival.