{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T17:06:41Z","timestamp":1789664801272,"version":"4.0.1"},"reference-count":41,"publisher":"American Society for Clinical Investigation","issue":"22","license":[{"start":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T00:00:00Z","timestamp":1763337600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82341026,82073163"],"award-info":[{"award-number":["82341026,82073163"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"National Key Research and Development Program of China","award":["No. 2022YFC2505400"],"award-info":[{"award-number":["No. 2022YFC2505400"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,11,17]]},"abstract":"<jats:p>\n                    Macrophage-mediated phagocytosis plays a critical role in the elimination of cancer cells and shaping antitumor immunity. However, the tumor-intrinsic pathways that regulate cancer cell sensitivity to macrophage-mediated phagocytosis remain poorly defined. In this study, we performed a genome-wide CRISPR screen in murine pancreatic cancer cells cocultured with primary macrophages and identified that disruption of the tumor-intrinsic pyrimidine synthesis pathway enhances phagocytosis. Mechanistically, we discovered that macrophages inhibit the pyrimidine salvage pathway in tumor cells by upregulating\n                    <jats:italic>Upp1<\/jats:italic>\n                    -mediated uridine degradation through cytokines TNF-\u03b1 and IL-1. This shift increased tumor cells\u2019 reliance on de novo pyrimidine synthesis. As a result, tumor cells with impaired de novo pyrimidine synthesis showed depleted UMP and displayed enhanced exposure of phosphatidylserine (PtdSer), a major \u201ceat-me\u201d signal, thereby promoting macrophage-mediated phagocytosis. In multiple pancreatic cancer models,\n                    <jats:italic>Cad<\/jats:italic>\n                    -deficient tumors exhibited markedly reduced tumor burden with increased levels of phagocytosis by macrophages. Importantly, the\n                    <jats:italic>Cad<\/jats:italic>\n                    -mediated suppression of pancreatic cancer was dependent on TAMs and cytokines IL-1 and TNF-\u03b1. Pharmacological inhibition of DHODH, which blocks de novo pyrimidine synthesis, similarly decreased tumor burden with enhanced phagocytosis in pancreatic cancer models. These findings highlight the critical role of the tumor-intrinsic pyrimidine synthesis pathway in modulating macrophage-mediated antitumor immunity, with potential therapeutic implications.\n                  <\/jats:p>","DOI":"10.1172\/jci193370","type":"journal-article","created":{"date-parts":[[2025,11,16]],"date-time":"2025-11-16T19:00:52Z","timestamp":1763319652000},"source":"Crossref","is-referenced-by-count":3,"title":["Targeting plasticity in the pyrimidine synthesis pathway potentiates macrophage-mediated phagocytosis in pancreatic cancer models"],"prefix":"10.1172","volume":"135","author":[{"given":"Jie","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Basic Medical Sciences, State Key Laboratory of Molecular Oncology, Tsinghua University, Beijing, China."},{"name":"Tsinghua-Peking Joint Centre for Life Sciences 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