Related Experiment Video
Updated: Mar 27, 2026
Studying the Effects of Tumor-Secreted Paracrine Ligands on Macrophage Activation using Co-Culture with Permeable Membrane Supports
Published on: November 28, 2019
Modulating tumor-associated macrophages through APP-CD74 blockade with IL4R-exosomes synergizes with PD-1 inhibition
Ou Chen1, Tong Liu2, Linlin Fu3
1Department of Clinical Laboratory, The Fourth Affiliated Hospital of China Medical University, Shenyang, China.
Abstract:
Gastric cancer (GC) is characterized by a highly immunosuppressive tumor microenvironment (TME), limiting the efficacy of immunotherapies. This study identifies the APP-CD74 signaling axis as a critical driver of M2-like tumor-associated macrophage (TAM) polarization in GC. Integrated single-cell RNA sequencing from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) datasets revealed selective enrichment of Amyloid Precursor Protein (APP)-CD74 signaling in immunosuppressive TAM subsets. Functional assays in THP-1-derived and murine bone marrow-derived macrophages confirmed that APP and CD74 activation promotes M2 polarization. In vivo, pharmacological inhibition of APP in GC-bearing mice repolarized TAMs toward the M1 phenotype, enhanced CD8⁺ T cell and NK cell responses, and significantly inhibited tumor growth. To enable targeted delivery, exosomes derived from M1 macrophages were engineered with IL4R-targeting ligands and loaded with APP-specific siRNA [IL4R-Exo(siCD74)], effectively targeting M2 macrophages and reversing their phenotype. In orthotopic GC models, IL4R-Exo(siCD74) markedly suppressed tumor progression. Strikingly, its combination with the immune checkpoint inhibitor Nivolumab synergistically boosted antitumor immunity and reshaped the immunosuppressive TME. These findings uncover the APP-CD74 axis as a novel immunoregulatory pathway in GC and provide a nanotherapeutic strategy leveraging macrophage plasticity to overcome immune resistance and enhance immunotherapeutic efficacy.
Insights
This study reveals the Amyloid Precursor Protein (APP)-CD74 signaling pathway drives immunosuppressive macrophages in gastric cancer (GC). Inhibiting APP and using engineered exosomes reverses this, enhancing immunotherapy and reducing tumor growth.
Area of Science:
- Immunology
- Oncology
- Cancer Biology
Background:
- Gastric cancer (GC) features an immunosuppressive tumor microenvironment (TME) hindering immunotherapy.
- Tumor-associated macrophages (TAMs) often adopt an M2-like phenotype, contributing to immune suppression in GC.
Purpose of the Study:
- To identify key drivers of M2-like TAM polarization in GC.
- To explore the APP-CD74 signaling axis in GC immunosuppression.
- To develop a novel nanotherapeutic strategy to overcome immune resistance in GC.
Main Methods:
- Integrated analysis of single-cell RNA sequencing data (GEO, TCGA).
- Functional assays using THP-1 and murine bone marrow-derived macrophages.
- In vivo studies in GC-bearing mice with pharmacological APP inhibition.
- Development and testing of engineered exosomes (IL4R-Exo(siCD74)) for targeted M2 TAM repolarization.
- Combination therapy with Nivolumab in orthotopic GC models.
Main Results:
- The APP-CD74 signaling axis was selectively enriched in immunosuppressive TAMs in GC.
- APP activation promoted M2 polarization in macrophages.
- Pharmacological APP inhibition in vivo repolarized TAMs to M1, enhanced anti-tumor immune cells (CD8+ T cells, NK cells), and inhibited tumor growth.
- Engineered IL4R-Exo(siCD74) targeted M2 macrophages, reversed their phenotype, and suppressed tumor progression in orthotopic models.
- Combination therapy with Nivolumab showed synergistic antitumor effects and reshaped the TME.
Conclusions:
- The APP-CD74 axis is a critical regulator of macrophage polarization and immunosuppression in GC.
- Targeting APP-CD74 signaling with engineered exosomes represents a promising nanotherapeutic strategy for GC.
- This approach enhances macrophage plasticity, overcomes immune resistance, and potentiates immunotherapy efficacy, particularly in combination with immune checkpoint inhibitors.
