Background 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.

Methods 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.

Results 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.

Conclusions 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.