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Tumor\u2010associated macrophages (TAMs) are among key drivers of this resistance. Phospholipase D3 (PLD3) is mainly expressed in macrophages, and PLD3+ macrophage (PLD3+Macro) influences immunotherapeutic efficacy and patient prognosis. We sought to define the role of PLD3 in regulating macrophage phenotypes, CRC progression, and immunotherapeutic response, and to identify potential agents target PLD3. Immunofluorescence revealed that the spatial infiltration dynamics of PLD3+Macro dictate immunotherapy resistance in CRC. We generated myeloid\u2010specific Pld3\u2010knockout mice. Using single\u2010cell RNA sequencing (scRNA\u2010seq) and flow cytometry, we delineated the impact of PLD3 on the tumor microenvironment (TME). RNA sequencing (RNA\u2010seq) and mass spectrometry were applied to explore the role of PLD3 in macrophages. By integrating molecular docking with tumor models, we assessed the therapeutic potential of targeting macrophage\u2010specific PLD3 in tumor progression and immunotherapy resistance. Collectively, PLD3 promotes tumor progression and immunotherapy resistance by modulating lysosomal\u2010AKT\u2010NF\u2010\u03baB axis, thereby driving macrophage senescence and anti\u2010inflammatory phenotype. This is accompanied by dysregulated crosstalk from macrophages to NK and T cells, ultimately forming an immunosuppressive TME. Abrine targets PLD3 in macrophages and effectively enhances immunotherapy response in CRC.<\/jats:p>","DOI":"10.1002\/advs.75730","type":"journal-article","created":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T07:57:32Z","timestamp":1779350252000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Targeting PLD3 Reverses the Immunosuppressive Niche by Reprogramming Tumor\u2010Associated Macrophages and Potentiates Antitumor Immunity"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-2035-6397","authenticated-orcid":false,"given":"Xingtu","family":"Qin","sequence":"first","affiliation":[{"name":"Department of General Surgery, Nanfang Hospital Southern Medical University Guangzhou Guangdong China"},{"name":"Guangdong Province Key Laboratory of Molecular Tumor Pathology Guangzhou Guangdong China"},{"name":"Guangdong Provincial Key Laboratory of Precision Medicine for 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