Macrophage- or neutrophil-expressed UPP1 drives tumor growth and immune suppression in the tumor microenvironment.

Uridine phosphorylase 1 (UPP1) has recently emerged as a metabolic regulator with critical roles in tumor cell biology. However, its expression pattern and functional significance in nonmalignant components of the tumor microenvironment (TME) remain largely unexplored. Here, we performed a comprehensive pan-cancer single-cell transcriptomic analysis revealing that UPP1 is highly expressed not only in tumor cells but also in tumor-associated macrophages (TAMs) and neutrophils (TANs). Clinically, UPP1 expression in TAMs and TANs correlates with poor prognosis and diminished response to immunotherapy across multiple cancer types. Mechanistically, UPP1 up-regulation could be driven by NF-κB signaling. Functionally, UPP1 reprograms macrophages toward a tumor-promoting phenotype, characterized by enhanced glycolysis, ATP-adenosine signaling activation, and increased production of immunosuppressive cytokines such as granulocyte colony-stimulating factor. In neutrophils, UPP1 also supports TAN polarization, influences neutrophil extracellular trap release, and contributes to broad immunosuppressive remodeling. In vivo, targeting UPP1 in macrophages or neutrophils reprograms the immune landscape and restrains tumor progression. Together, our findings uncover a previously underappreciated role of UPP1 in nonmalignant immune populations and establish it as a key immune mediator within the TME, offering a potentially promising therapeutic target for enhancing antitumor immunity.