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<p>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.</p>

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Modulating tumor-associated macrophages through APP-CD74 blockade with IL4R-exosomes synergizes with PD-1 inhibition in gastric cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月25日

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  • Ou Chen,
  • Tong Liu,
  • Linlin Fu,
  • Jinggui Li,
  • Yu Wang,
  • Wei Wang,
  • Jun Liu,
  • Yanqing Wen

摘要

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.