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Alpha\/beta hydrolase domain\u2010containing protein 17C (ABHD17C) is a kind of depalmitoyltransferase and its roles in tumor immunology remain largely unclear. This study aims to investigate the role of ABHD17C in the macrophage\u2010mediated innate immunity in pancreatic cancer (PC). Clinically, ABHD17C is abnormally overexpressed in PC tissues and associated with poor prognosis in patients. Using orthotopic cell\u2010derived xenograft \u2010based NSG murine models, we observed that ABHD17C\u2010mediated macrophage phagocytic resistance promotes tumor growth in a depalmitoylation\u2010dependent manner. Mechanistically, ABHD17C\u2010mediated depalmitoylation of B cell lymphoma 6 member B protein (BCL6B) at Cys442 impedes importin\u2010\u03b1\/\u03b2\u2010mediated nuclear translocation of BCL6B and drives its ubiquitination\u2010dependent degradation in the cytoplasm. The deficiency of nuclear BCL6B attenuates transcriptional repression of the anti\u2010phagocytic signal CD24, increases its expression, enables PC cells to evade macrophage attack, and ultimately promoting PC progression. Therefore, this study elucidates the mechanism by which the depalmitoyltransferase ABHD17C protects tumor cells from macrophage phagocytosis, which highlights the therapeutic potential of targeting the ABHD17C\/BCL6B\/CD24 signaling axis by macrophage\u2010mediated innate immune pathway in PC.<\/jats:p>","DOI":"10.1002\/advs.75757","type":"journal-article","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T15:11:36Z","timestamp":1779203496000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["ABHD17C\u2010Mediated S\u2010Depalmitoylation of BCL6B Enhances CD24 Transcription to Resist Macrophage Phagocytosis in Pancreatic Cancer"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5278-0788","authenticated-orcid":false,"given":"Yalu","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of General Surgery The First Affiliated Hospital of USTC Division of 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