Uridine phosphorylase 1 (UPP1): an emerging regulator in Tumorigenesis, immunity, and beyond

Uridine phosphorylase 1 (UPP1) is a key enzyme in the pyrimidine salvage pathway that catalyzes the reversible conversion of uridine into uracil and ribose-1-phosphate. While historically viewed as a housekeeping enzyme involved in nucleotide homeostasis, UPP1 has recently emerged as a context-dependent regulator that integrates cellular metabolism, oncogenic signaling, and immune modulation. Accumulating evidence suggests that UPP1 is frequently upregulated across a broad spectrum of cancers, functioning as a metabolic node that enables tumor cells to sustain growth under nutrient stress by diverting uridine-derived ribose into central carbon metabolism. Beyond its metabolic role, UPP1 also functions as a signaling co-regulator, engaging pathways such as the PI3K/AKT, NF-κB, and mTOR pathways to promote tumor proliferation, immune evasion, and therapeutic resistance. Notably, UPP1 exerts profound effects on the tumor immune microenvironment by shaping cytokine production, immune checkpoint expression, and the functional states of diverse immune and stromal cell populations, thereby facilitating immune suppression and metastatic progression. In parallel, emerging studies reveal that UPP1 plays important roles in non-neoplastic inflammatory conditions, including psoriasis, sepsis, and acute lung injury, highlighting its functional duality across malignant and inflammatory contexts. UPP1 expression is tightly controlled by multilayered regulatory mechanisms involving transcription factors, epigenetic modifications, non-coding RNAs, and extracellular cues, enabling its dynamic adaptation to metabolic and inflammatory stress. In this review, we synthesize recent advances to propose a unified conceptual framework in which UPP1 functions as an immunometabolic regulator rather than a simple metabolic enzyme. We discuss how its context-dependent activities contribute to tumorigenesis, immune remodeling, and inflammatory pathology, and highlight how targeting the UPP1-centered immunometabolic network may offer a promising intervention strategy to overcome resistance to cancer immunotherapy and modulate severe inflammatory responses.