Epithelial SLC25A20 Deficiency Drives Immunosuppressive Neutrophil Remodeling via ARG1 Palmitoylation to Promote Colorectal Cancer

Abstract

ABSTRACT While lipid metabolic reprogramming is increasingly recognized as a substantial driver of tumor microenvironment (TME) remodeling, how dysregulated fatty acid oxidation (FAO) contributes to immune evasion in colorectal cancer (CRC) progression remains obscure. Here, we identify the mitochondrial carnitine‐acylcarnitine translocase solute carrier 25 member 20 (SLC25A20), an essential conduit for FAO, as a key regulator of CRC progression through neutrophil phenotypic remodel. Mechanistically, SLC25A20 deficiency in CRC cells blunts mitochondrial long‐chain fatty acid (LCFA) import and FAO, triggering the release of LCFAs into the TME. This lipid‐rich niche not only vigorously recruits tumor‐associated neutrophils (TANs), but intrinsically programs them toward an immunosuppressive phenotype. Specifically, tumor‐derived LCFAs enforce arginase‐1 (ARG1) protein stability in TANs via ZDHHC18‐mediated palmitoylation. This distinct post‐translational modification (PTM) is indispensable for TAN‐mediated CD8+ T cell suppression and subsequent tumor immune evasion. Importantly, genetic or pharmacological blockade of this palmitoylation axis in TANs reinvigorates antitumor immunity and abolishes the tumor‐promoting effects of SLC25A20 deficiency. Collectively, our findings uncover a novel lipid‐driven metabolic symbiosis between CRC and neutrophils, highlighting the ZDHHC18‐ARG1 palmitoylation axis as a promising therapeutic strategy for CRC intervention.