CDS1 deficiency promotes colorectal cancer progression by suppressing CDP-DAG-induced ferroptosis in MDSCs.

Dysregulation of phospholipid metabolism has been increasingly recognized as a critical contributor to colorectal cancer (CRC) progression; however, the key molecular determinants governing this process remain incompletely defined. In this study, we identify CDP-diacylglycerol synthetase 1 (CDS1) as a central player in CRC pathogenesis and systematically elucidate its functional mechanism. Through an integrated approach combining bioinformatic analysis of TCGA datasets with extensive experimental validation using in vitro cellular models and in vivo tumor systems, we demonstrate that CDS1 expression is significantly downregulated in CRC tissues. Functional studies reveal that loss of CDS1 promotes tumor growth in an immune microenvironment-dependent manner. Mechanistically, CDS1 catalyzes the synthesis and secretion of CDP-diacylglycerol (CDP-DAG), which binds to transcription factor CEBPG and induces ferroptosis in myeloid-derived suppressor cells (MDSCs). This process effectively alleviates MDSC-mediated immunosuppression, leading to enhanced infiltration and activation of cytotoxic T lymphocytes within the tumor microenvironment. Furthermore, we show that CDP-DAG exhibits synergistic effects with anti-PDL1 therapy, significantly enhancing antitumor immune responses. These findings establish the CDS1/CDP-DAG signaling axis as a novel immunometabolic checkpoint in CRC, providing important insights into the interplay between phospholipid metabolism and antitumor immunity. The study highlights the potential of targeting this pathway for both diagnostic and therapeutic applications in CRC immunotherapy.