Upregulation of macrophage UPP1 promotes lung adenocarcinoma metastasis through an mtROS-cGAS-NLRP3 inflammasome axis.
TL;DR
A macrophage-specific immunometabolic circuit in which UPP1-driven mitochondrial stress activates the mtROS-cGAS-NLRP3 axis, promoting IL-1β-dependent macrophage-tumor crosstalk and metastatic progression is identified.
Abstract
Metastasis and immunosuppression remain major barriers to effective treatment of lung adenocarcinoma (LUAD), yet the metabolic mechanisms governing the pro-tumor functions of tumor-associated macrophages are incompletely understood. In this study, we identified Uridine Phosphorylase 1 (UPP1) as a macrophage-enriched metabolic regulator associated with LUAD progression. By integrating single-cell RNA sequencing with clinical cohort analyses, we found that UPP1 was preferentially expressed in tumor-associated macrophages and was associated with adverse clinical outcomes. Functional and mechanistic studies demonstrated that dysregulated UPP1 disrupted nucleotide homeostasis, leading to mitochondrial reactive oxygen species accumulation and mitochondrial DNA leakage. These mitochondrial stress signals activated the cGAS-STING pathway, which preferentially engaged NLRP3 inflammasome signaling rather than canonical antiviral responses. Consequently, macrophages underwent pyroptosis and released elevated levels of interleukin-1β (IL-1β). Through paracrine signaling, macrophage-derived IL-1β promoted epithelial-mesenchymal transition in LUAD cells and enhanced their invasive capacity in vitro. Consistent with these findings, co-injection of UPP1-overexpressing macrophages significantly increased spontaneous lung metastasis in vivo. Clinically, elevated UPP1 expression served as an independent predictor of poor survival. Furthermore, pharmacological blockade of this signaling cascade or neutralization of IL-1β attenuated macrophage-induced malignant phenotypes in tumor cells, highlighting the therapeutic relevance of this pathway. Collectively, our findings identify a macrophage-specific immunometabolic circuit in which UPP1-driven mitochondrial stress activates the mtROS-cGAS-NLRP3 axis, promoting IL-1β-dependent macrophage-tumor crosstalk and metastatic progression. These results suggest that UPP1 may serve as both a prognostic biomarker and a potential therapeutic target in LUAD.