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

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.