ABHD17C‐Mediated S‐Depalmitoylation of BCL6B Enhances CD24 Transcription to Resist Macrophage Phagocytosis in Pancreatic Cancer

ABSTRACT The phagocytic function of macrophages plays a crucial role in the innate immune response against tumors. Alpha/beta hydrolase domain‐containing 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‐mediated innate immunity in pancreatic cancer (PC). Clinically, ABHD17C is abnormally overexpressed in PC tissues and associated with poor prognosis in patients. Using orthotopic cell‐derived xenograft ‐based NSG murine models, we observed that ABHD17C‐mediated macrophage phagocytic resistance promotes tumor growth in a depalmitoylation‐dependent manner. Mechanistically, ABHD17C‐mediated depalmitoylation of B cell lymphoma 6 member B protein (BCL6B) at Cys442 impedes importin‐α/β‐mediated nuclear translocation of BCL6B and drives its ubiquitination‐dependent degradation in the cytoplasm. The deficiency of nuclear BCL6B attenuates transcriptional repression of the anti‐phagocytic 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‐mediated innate immune pathway in PC.