PLA2G16‐Mediated Tetracosatetraenoic Acid Rewires Fatty Acid Oxidation to Impair CD8 + T Cell Immune Function in Promoting Breast Cancer Lung Metastasis

Abstract Tumor‐related metabolites in the tumor microenvironment may induce immune dysfunction, leading to malignant progression and metastasis of tumors. Here, it is demonstrated that tumoral PLA2G16, a phospholipase catalyzes phospholipids to generate free fatty acid (FFA) or lysophosphatidic acid (LPA), is an important contributor to triple‐negative breast cancer (TNBC) lung metastasis in an immune‐dependent pattern by improving tetracosatetraenoic acid (C24:4 (n‐6)) accumulation in the early metastatic niche of lung and impairing immune function of pulmonary CD8 + T cells. C24:4 (n‐6) induces nuclear import of PPARα in pneumal CD8 + T cells, which regulates the transcription of Cpt1a, Dgat1, Cd36 , and Fabp1 , leading to the activation of fatty acid oxidation (FAO). The robust FAO results in suppression of CD8 + T cells. Genetically depleting PPARα in mice, pharmacologically inhibiting C24:4 (n‐6)‐induced PPARα in the nucleus or directly suppressing PPARα activity effectively attenuates PLA2G16‐C24:4 (n‐6) axis‐based immune dysfunction of CD8 + T cells and their according anti‐tumor activities. These results imply that PLA2G16‐mediated C24:4 (n‐6) accumulation in the lung acts as a metabolic disorder to CD8 + T cell antitumor activity and highlights a critical role of PLA2G16 in promoting TNBC lung metastasis. Targeting PLA2G16 and combination with anti‐PD‐1‐based immunotherapy may be an effective strategy for clinical tumor immunotherapy.