Targeting plasticity in the pyrimidine synthesis pathway potentiates macrophage-mediated phagocytosis in pancreatic cancer models
Jie Zhao, Xinghao Li, Xinyu Li, Pengfei Ren, Yilan Wu, Hao Gong, Lijian Wu, Junran Huang, Saisai Wang, Ziwei Guo, Mo Chen, Zexian Zeng, Deng Pan
Jie Zhao, Xinghao Li, Xinyu Li, Pengfei Ren, Yilan Wu, Hao Gong, Lijian Wu, Junran Huang, Saisai Wang, Ziwei Guo, Mo Chen, Zexian Zeng, Deng Pan
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Research Article Immunology Metabolism Oncology

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

Abstract

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 Upp1-mediated uridine degradation through cytokines TNF-α and IL-1. This shift increased tumor cells’ 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 “eat-me” signal, thereby promoting macrophage-mediated phagocytosis. In multiple pancreatic cancer models, Cad-deficient tumors exhibited markedly reduced tumor burden with increased levels of phagocytosis by macrophages. Importantly, the Cad-mediated suppression of pancreatic cancer was dependent on TAMs and cytokines IL-1 and TNF-α. 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.

Authors

Jie Zhao, Xinghao Li, Xinyu Li, Pengfei Ren, Yilan Wu, Hao Gong, Lijian Wu, Junran Huang, Saisai Wang, Ziwei Guo, Mo Chen, Zexian Zeng, Deng Pan

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Figure 8

Human relevance for targeting de novo pyrimidine synthesis pathway in the presence of cytokine secrete macrophages.

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Human relevance for targeting de novo pyrimidine synthesis pathway in th...
(A) Heatmap showing the correlation of UPP1 expression and macrophage infiltration (top panel) and the correlation of UPP1 expression and TNF and IL1B levels (bottom panel) in the TCGA cohort in TCGA bulk RNA-Seq datasets. (B) Single-cell analysis of the correlation between UPP1 expression level in tumor cells and TNF-α or IL-1β expression levels of macrophages in pancreatic cancer cohort. The left panel shows the strategy for single-cell analysis. Created using BioRender.com. The right panels show the correlation between UPP1 and TNF-α/IL-1β. (C–E) Overall survival of TCGA pancreatic adenocarcinoma based on the level of UMPS expression under the conditions of TNF-α expression level (C), IL-1β expression level (D), or estimated level of M1-like macrophage infiltration (E). Statistical analyses were performed by linear regression model (B) and log-rank test (C–E).