Immune checkpoint blockade therapies have transformed the landscape of cancer care, but durable clinical responses are achieved in only a subset of patients. To identify genes that can contribute to immunotherapy resistance, a genome-wide CRISPR screen was performed. Selection for mutants that are resistant to T cell-mediated killing identified the gene encoding Decr2, a peroxisomal 2,4-dienoyl-CoA reductase. We show that Decr2 in tumor cells participates in CD8+ T cell-mediated tumor cell killing and that Decr2 knockdown reduces the efficacy of anti-PD-L1 therapy in vivo. Knocking down Decr2 expression resulted in diminished ferroptosis that was associated with reduced induction of polyunsaturated ether phospholipids. Analysis of tumor RNA sequencing data from patients with melanoma revealed that upregulation of Decr2 was associated with anti-PD-1 efficacy, and patients with Decr2 gene deletions showed worse clinical outcomes. Our results identify Decr2 as a regulator of immunomediated tumor cell killing, with implications for improving immunotherapy efficacy.