%0 Journal Article
%T STAB1⁺ Macrophages Drive Immunosuppressive Efferocytosis in Colon Adenocarcinoma: Insights from Integrated Histopathologic and Transcriptomic Analysis
%A Andreas Nikolaus Schmid
%A Lukas Ferdinand Keller
%J Journal of Medical Sciences and Interdisciplinary Research
%@ 3108-4826
%D 2022
%V 2
%N 2
%R 10.51847/4Peiu63ffW
%P 89-110
%X Colon adenocarcinoma (COAD) shows poor responsiveness to immunotherapy largely because its tumor microenvironment (TME) is immunologically “cold.” Efferocytosis plays a critical role in shaping the TME; however, its underlying mechanisms and clinical relevance in COAD remain poorly understood. We integrated transcriptomic data, histopathological images, and clinical information from 387 patients with COAD. Image features were derived using ResNet50 and CellProfiler, and a multimodal machine learning model was then developed to assess prognostic risk. In addition, bulk RNA sequencing, single-cell RNA sequencing, and spatial transcriptomics were jointly analyzed to systematically delineate efferocytosis-related immune cell populations and their associated signaling pathways. The efferocytosis-driven risk model showed robust prognostic accuracy at multiple time points and functioned independently of established clinical factors. From a mechanistic perspective, we identified a population of STAB1⁺ tumor-associated macrophages (TAMs) that was enriched in COAD tumors and characterized by elevated efferocytosis capacity, M2-like polarization, and activation of mTORC1 signaling. In vitro experiments demonstrated that STAB1 was required for IL-4–mediated M2 polarization, and that suppressing STAB1 reduced the development of immunosuppressive TAMs. Analyses using single-cell and spatial transcriptomics further indicated that this macrophage subset was transcriptionally distinct and became more abundant after neoadjuvant treatment. This work presents a multimodal prognostic framework that combines histopathological image analysis with molecular data, and for the first time highlights the central role of STAB1⁺ tumor-associated macrophages in driving an immunosuppressive tumor microenvironment through efferocytosis and mTORC1 signaling. Our results offer a clinically relevant tool for risk stratification as well as a promising therapeutic target. Inhibiting STAB1 may help expand the effectiveness of immunotherapy in COAD patients who show poor responses to immune checkpoint inhibitors.
%U https://smerpub.com/article/stab1-macrophages-drive-immunosuppressive-efferocytosis-in-colon-adenocarcinoma-insights-from-inte-eifixcbpv1h2eyk