The Critical Role of APOE+ Macrophages in the Immune Microenvironment and Prognosis of Lung Adenocarcinoma

Abstract

The immunoregulatory functions and clinical implications of APOE+ macrophages within the tumour microenvironment of lung adenocarcinoma remain incompletely defined. In this study, single-cell transcriptome analysis revealed distinct subsets of APOE+ macrophages, and subsequent CellChat analyses highlighted that these cells predominantly interact with other components of the tumour microenvironment via MIF-(CD74+CXCR4) and MIF-(CD74+CD44) signalling pathways, thereby contributing to the establishment of an immunosuppressive milieu. Integrating mutation profiles with multiple machine learning techniques, we developed an APOE+ Macrophage-related Risk Model (ARM) through a combination of RSF and Ridge approaches, achieving the highest prognostic accuracy (C-index) among all tested algorithms. The robustness and predictive value of the ARM model were validated across seven public cohorts and three prospective immunotherapy cohorts. Patients classified in the low-ARM group consistently exhibited better prognoses, as demonstrated by survival analyses, ROC curves and PCA discrimination. Additionally, multiplex immunofluorescence analysis in the in-house cohort confirmed significantly decreased infiltration of CD4+, CD8+ and CD20+ immune cells in the high-ARM group, further supporting a more pronounced immunosuppressive microenvironment in these patients. Collectively, our findings not only clarify the critical role of APOE+ macrophages in shaping the immune landscape and prognosis of lung adenocarcinoma, but also provide a validated, practical risk model for individualised patient prognostication and clinical management.