biostudies-literatureGan YNational Natural Science Foundation of ChinaOutstanding Professorship Program of Chongqing Medical Universitye10224https://www.ebi.ac.uk/biostudies/studies/S-EPMC12866795biostudies-literatureUnknown13(6)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.Advanced science (Weinheim, Baden-Wurttemberg, Germany)PLA2G16-Mediated Tetracosatetraenoic Acid Rewires Fatty Acid Oxidation to Impair CD8<sup>+</sup> T Cell Immune Function in Promoting Breast Cancer Lung Metastasis.PMC1286679582273295R1000582372823NSFC82173155Lang LGuo YLiu MLu ZTan DHou YMeng DLuo JWang RDai PGan YChang CChen STang XfalsePLA2G16-Mediated Tetracosatetraenoic Acid Rewires Fatty Acid Oxidation to Impair CD8<sup>+</sup> T Cell Immune Function in Promoting Breast Cancer Lung Metastasis.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.2026-01-01T00:00:00Z2026 Jan2026-07-15T06:08:45.058Z2026-06-30T03:21:38.546ZS-EPMC128667954124192010.1002/advs.202510224