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

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.