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This study investigates the efficacy of self\u2010assembled M2pep\u2010Cs NPs\/Plerixafor nanoparticles in suppressing GC by targeting the CXCL12\u2013CXCR4 signaling pathway and reprogramming tumor\u2010associated macrophages (TAMs) to enhance anti\u2010tumor immunity. The nanoparticles\u2019 physicochemical properties and biocompatibility are assessed using transmission electron microscopy, dynamic light scattering, and biological assays. A GC mouse model is established, followed by histological and immunohistochemical analyses to evaluate tumor apoptosis and proliferation. Multi\u2010omics approaches, including transcriptomics, proteomics, and metabolomics, identify key genes and pathways affected by treatment. Flow cytometry and ELISA quantify immune activation markers; while, cell migration and invasion assays evaluate tumor suppression effects. The results demonstrate that M2pep\u2010Cs NPs\/Plerixafor effectively modulates the tumor microenvironment, suppressing GC progression by reprogramming TAMs through CXCL12\u2013CXCR4 inhibition, enhancing immune recognition and T cell responses. This study provides mechanistic insights and highlights the potential of nanoparticle\u2010based immunotherapy for GC, offering a promising avenue for clinical translation.<\/jats:p>","DOI":"10.1002\/advs.202500225","type":"journal-article","created":{"date-parts":[[2025,6,19]],"date-time":"2025-06-19T11:12:48Z","timestamp":1750331568000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Nanoparticle\u2010Mediated CXCL12\u2013CXCR4 Inhibition Reprograms Macrophages and Suppresses Gastric Carcinoma"],"prefix":"10.1002","volume":"12","author":[{"given":"Qianqian","family":"Cao","sequence":"first","affiliation":[{"name":"Cancer Center, The Second Hospital Cheeloo College of Medicine Shandong University  Jinan 250033 P. R. 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