IDDF2024-ABS-0391 ABHD12 remodels phospholipid metabolism to suppress ferroptosis and mediate immunotherapy resistance in CRC

<h3>Background</h3> Metabolic reprogramming of tumor plays a crucial role in tumorigenesis and immune environment remodeling. The Abhydrolase domain containing 12 (ABHD12), a lysophosphatidylserine (lyso-PS) lipase, is indispensable for phospholipid metabolism. However, the role and underlying mechanisms of ABHD12 in remodeling the immune environment remain unknown in CRC. <h3>Methods</h3> Metabolic genome-scale CRISPR/Cas9 knockout library screen was utilized in normal and immune-sufficient mice to screen immune-related genes of CRC. The metabolic mechanism of ABHD12 was investigated by RNA sequencing, lipidomics, luciferase reporter assay, and lipid peroxidation assay. The interaction with T cells was determined by T cell cytotoxicity assay, cytometry, and T cell depletion in vivo. Immunohistochemical staining in tissue microarray from Sun Yat-sen University Cancer Center’s CRC patients was applied to assess the relationship between ABHD12-expression with prognosis, and immunotherapy resistance. <h3>Results</h3> Utilizing a metabolic genome-scale CRISPR/Cas9 knockout library screen, we identified that ABHD12 effectively protected CRC cells from immune pressure. Mechanistically, ABHD12 mediates the hydrolysis of phospholipid-containing polyunsaturated fatty acid (PUFA), thereby preventing lipid peroxidation and subsequently suppressing ferroptosis. ABHD12 knockdown induced cellular ferroptosis, as a kind of immunogenic cell death, increased CD8⁺ T cell infiltration, and enhanced the efficacy of immune checkpoint therapies. Moreover, our study determined that ABHD12 is upregulated by activated β-catenin signaling pathways. Assessment of immunohistochemical tissue assay demonstrated that higher ABHD12 expression level correlated with poor prognosis and higher probability of immunotherapy resistance. <h3>Conclusions</h3> Overall, our study revealed the function of ABHD12 in remodeling the immune environment, which acts as a ferroptosis inhibitor via catalyzing PUFA-containing phospholipid to decrease lipid peroxidation level and mediates immune evasion, suggesting that ABHD12 is a potential therapeutic target to improve the effects of immunotherapy.