The study investigates the role of Uridine Phosphorylase I (UPPI) in lung adenocarcinoma (LUAD) progression, focusing on its impact on the tumor microenvironment (TME). Using single-cell RNA sequencing (scRNA-seq) data from 117 LUAD patient samples, the researchers identified a cluster of UPPI-high tumor cells that are strongly associated with immunosuppressive components in the TME. These cells, primarily found at the invasive front of tumors, upregulate the expression of various immunosuppressive cytokines, particularly TGF-β1, and PD-L1 through the PI3K/AKT/mTOR pathway, leading to the suppression of CD8+ T cells. CyTOF analysis further supports these findings, showing that UPPI-high tumor cells contribute to an immunosuppressive TME. Additionally, patient-derived organoids (PDOs) reveal that UPPI-high tumors are more sensitive to Bosutinib and Dasatinib. The study highlights the immunosuppressive role of UPPI in LUAD and suggests potential therapeutic strategies based on these findings.The study investigates the role of Uridine Phosphorylase I (UPPI) in lung adenocarcinoma (LUAD) progression, focusing on its impact on the tumor microenvironment (TME). Using single-cell RNA sequencing (scRNA-seq) data from 117 LUAD patient samples, the researchers identified a cluster of UPPI-high tumor cells that are strongly associated with immunosuppressive components in the TME. These cells, primarily found at the invasive front of tumors, upregulate the expression of various immunosuppressive cytokines, particularly TGF-β1, and PD-L1 through the PI3K/AKT/mTOR pathway, leading to the suppression of CD8+ T cells. CyTOF analysis further supports these findings, showing that UPPI-high tumor cells contribute to an immunosuppressive TME. Additionally, patient-derived organoids (PDOs) reveal that UPPI-high tumors are more sensitive to Bosutinib and Dasatinib. The study highlights the immunosuppressive role of UPPI in LUAD and suggests potential therapeutic strategies based on these findings.