This study investigates the role of UPP1 in promoting lung adenocarcinoma (LUAD) progression by inducing an immunosuppressive tumor microenvironment (TME). Using integrative single-cell RNA sequencing (scRNA-seq) data from 117 LUAD patient samples, the researchers identified a cluster of UPP1-high tumor cells located at the invasive front of tumors, which are strongly associated with immunosuppressive components in the TME. Cytokine array analysis revealed that UPP1 upregulation in tumor cells increases the release of immunosuppressive cytokines, with TGF-β1 being particularly prominent. Additionally, UPP1 upregulation enhances PD-L1 expression through the PI3K/AKT/mTOR pathway, which suppresses CD8+ T cells. CyTOF analysis further supports the role of UPP1 in shaping an immunosuppressive TME. Patient-derived organoids (PDOs) showed that UPP1-high tumors are more sensitive to Bosutinib and Dasatinib. The study highlights the immunosuppressive role of UPP1 in LUAD and suggests that targeting UPP1 could improve immunotherapy outcomes. UPP1 is involved in uridine metabolism and has been linked to tumor progression. The findings suggest that UPP1-high tumors are more resistant to immunotherapy and that inhibiting UPP1 could enhance the efficacy of anti-PD-L1 therapies. Bioinformatics analysis identified Bosutinib and Dasatinib as potential therapeutic agents for UPP1-high tumors. The study provides insights into the molecular mechanisms of LUAD and may lead to the development of personalized treatment strategies.This study investigates the role of UPP1 in promoting lung adenocarcinoma (LUAD) progression by inducing an immunosuppressive tumor microenvironment (TME). Using integrative single-cell RNA sequencing (scRNA-seq) data from 117 LUAD patient samples, the researchers identified a cluster of UPP1-high tumor cells located at the invasive front of tumors, which are strongly associated with immunosuppressive components in the TME. Cytokine array analysis revealed that UPP1 upregulation in tumor cells increases the release of immunosuppressive cytokines, with TGF-β1 being particularly prominent. Additionally, UPP1 upregulation enhances PD-L1 expression through the PI3K/AKT/mTOR pathway, which suppresses CD8+ T cells. CyTOF analysis further supports the role of UPP1 in shaping an immunosuppressive TME. Patient-derived organoids (PDOs) showed that UPP1-high tumors are more sensitive to Bosutinib and Dasatinib. The study highlights the immunosuppressive role of UPP1 in LUAD and suggests that targeting UPP1 could improve immunotherapy outcomes. UPP1 is involved in uridine metabolism and has been linked to tumor progression. The findings suggest that UPP1-high tumors are more resistant to immunotherapy and that inhibiting UPP1 could enhance the efficacy of anti-PD-L1 therapies. Bioinformatics analysis identified Bosutinib and Dasatinib as potential therapeutic agents for UPP1-high tumors. The study provides insights into the molecular mechanisms of LUAD and may lead to the development of personalized treatment strategies.