ORIGINAL RESEARCH article
Front. Oncol.
Sec. Gastrointestinal Cancers: Gastric and Esophageal Cancers
This article is part of the Research TopicArtificial Intelligence in Immunotherapy for Gastrointestinal Cancers: From Prediction to Precision MedicineView all 3 articles
The Identification of LA-Tumor Associated Macrophages in Immune Modulation via Amyloid-beta Precursor Protein/CD74 Signal Pathway in Gastric Cancer: A Predictive Module and Machine Learning
Provisionally accepted
- 1The First Affiliated Hospital of Anhui Medical University, Hefei, China
- 2Anhui Medical University School of Basic Medical Sciences, Hefei, China
- 3Anhui Medical University, Hefei, China
- 4First Affiliated Hospital of Anhui Medical University, Hefei, China
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Background: Tumor-associated macrophages (TAMs) play a critical role in cancer immune microenvironment, modulating immune evasion. The prognostic role of TAMs gives insights into the immune landscape and therapeutic targets in gastric cancer (GC). Methods: GC microenvironment was analyzed via single-cell and bulk RNA-seq data from public databases. TAM subtypes were then identified via dimensionality reduction and annotation under quality control. TAM differentiation and function were evaluated by pseudo-time analysis, cell communication, molecular docking, and key gene enrichment. A predictive model based on LA-TAM was established. Amyloid-β precursor protein (APP) expression level and its effect on macrophage programmed death-1 (PD-1) expression was validated in vitro. Results: In GC microenvironment, epithelial cells and fibroblasts were downregulated, while B cells, CD8⁺ T cells and myeloid cells were enriched. Among TAM subtypes, LA-TAM exhibited the potential of differentiation, metabolic reprogramming, and high plasticity. When LA-TAM interacts with endothelial cells, APP/Collagen pathway was activated, in which PD-1 expression was up-regulated by APP/CD74 activation. The LA-TAM-based predictive model showed significant performance among multiple cohorts (C-index >0.5, HR=1.63, p<0.001). APP positively correlated with PD-1 expression. In GC THP-1 monocytes, APP was enriched and stimulated PD-1 expression. Conclusion: LA-TAM plays a key role in immune suppression and metabolic regulation in GC. Its key genes form a high-precision prognosis model, and endothelial cell-expressed APP may promote immune evasion by enhancing macrophage PD-1 expression, suggesting a potential target for immunotherapy.
Keywords: gastric cancer, Immune Evasion, machine learning, predictive biomarkers, Tumor-associated macrophages
Received: 23 Nov 2025; Accepted: 09 Dec 2025.
Copyright: © 2025 Wang, An, Wang, Wei and Dai. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Zhi-Jian Wei
Ying Dai
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