Engineered Inflammation-Triggering Macrophages (MacTrigger) Synergize Anti-CD47 Immunotherapy While Sparing Normal Tissues.

CD47 has attracted considerable attention as a therapeutic immune checkpoint target; however, its clinical efficacy as monotherapy remains limited, mainly due to an M2-rich tumor environment. These limitations highlight the need for combination strategies capable of achieving synergistic anti-tumor effects. We previously developed engineered macrophages, termed MacTrigger, that release tumor necrosis factor-α upon polarization toward the M2 phenotype. By exploiting intrinsic macrophage properties-tumor homing and context-dependent polarization-MacTrigger is designed to induce inflammation selectively within the tumor tissues. Here, we investigated whether MacTrigger could synergistically enhance the therapeutic effects of anti-CD47 antibody (aCD47) while minimizing side effects. Temporal analysis revealed a delayed but pronounced increase in M1 macrophages within tumors following MacTrigger administration, indicating sustained immune reprogramming of the tumor tissues. Guided by this kinetic profile, we evaluated combination therapy with MacTrigger and aCD47 in tumor-bearing mice. While aCD47 monotherapy exhibited minimal anti-tumor effects, the combination treatment induced synergistic tumor suppression, prolonged survival, and reduced tumor cell proliferation. Notably, no systemic toxicity or inflammatory responses were detected in normal tissues. The synergistic efficacy was confined to tumor sites, consistent with spatially restricted inflammatory activation induced by MacTrigger. These findings establish MacTrigger as a tumor-selective inflammatory amplifier that overcomes resistance to CD47 blockade and provides a promising cell-based strategy to enhance aCD47 immunotherapy.