Targeting plasticity in the pyrimidine synthesis pathway potentiates macrophage-mediated phagocytosis in pancreatic cancer models

Macrophage-mediated phagocytosis plays a pivotal role in eradicating cancer cells and modulating anti-tumor immunity. Yet, the mechanisms through which cancer cells evade phagocytosis remain elusive. We employed a genome-wide CRISPR screen in murine pancreatic cancer cells co-cultured with macrophages and discovered that disabling the tumor-intrinsic pyrimidine synthesis pathway (specifically Cad, Dhodh, and Umps) leads to enhanced phagocytosis by macrophages. Mechanistically, macrophages suppress the UMP salvage pathway in tumor cells, increasing their dependence on de novo UMP synthesis. This suppression resulted in tumor cells with impaired de novo pyrimidine synthesis becoming more susceptible to apoptosis in the presence of macrophages, thereby enhancing macrophage-mediated elimination, both in vitro and in mouse models. Mechanistically, we show that pro-inflammatory cytokines released by macrophages, including TNFα and IL-1, are essential for upregulating Upp1 and decrease UMP pool in tumor cells. Thus, our findings uncover how tumor pyrimidine metabolism pathway shape their sensitivity to macrophage-mediated elimination.