Linoleic acid promotes TF expression through PPAR-α, which leads to tumor progression in primary pulmonary lymphoepithelioma-like carcinoma

Primary pulmonary lymphoepithelioma-like carcinoma (pLELC) is a relatively uncommon variant of primary non-small cell lung cancer, and its etiology is still largely unexplored. Objective: The aim of this study is to investigate the underlying mechanisms and potential therapeutic targets associated with pLELC. The patients diagnosed with advanced pLELC were retrospectively collected and subjected to proteomics and metabonomics analysis. Finally, a patient-derived xenograft (PDX) model of pLELC xenograft was constructed for validation. The results of the data-independent acquisition(DIA) quantitative analysis revealed that the expression of tissue factor (TF) protein was found to be upregulated in pLELC. Furthermore, it was observed that TF protein played a role in iron death, hypoxia-inducible factor-1 (HIF-1) signalling pathway, and leukocyte transendothelial migration. Untargeted metabonomics analysis revealed the presence of major metabolites, namely linoleic acid (LA), free fatty acid (16:0), and histidine. LA has been found to contribute to the progression of tumors by promoting the infiltration of M2 tumor-associated macrophages and inhibiting the infiltration of natural killer(NK) cells. However, this effect can be reversed by the TF inhibitor Tisotumab. LA enhances the expression of TF through peroxisome proliferator-activated receptor (PPAR)-α, and the malignancy caused by LA can be counteracted by TF inhibitors.The findings of this study suggest that LA has the ability to alter the tumor microenvironment in pLELC by upregulating TF expression through PPAR-α. These results indicate that TF could potentially serve as a therapeutic target for pLELC.