ALOX15-Mediated 15-HETE Uptake Drives Lung Cancer Cells Ferroptosis and Enhances CD8+ T Cell Immunity in Lung Cancer

ALOX15 exerts tumor suppressor in numerous cancers. However, the role of ALOX15 in lung cancer is scarcely reported. This study aimed to investigate the role of ALOX15 in lung cancer. GSE225620 was used to analyzed the differentially expressed genes in lung cancer patients treated with 5-FU. Gene expression was determined using RT-qPCR, Western blot, and immunofluorescence. Ferroptosis markers were analyzed using ELISA assays. Cytokine release was determined using flow cytometry. Cellular functions were analyzed using CCK-8, transwell assay, PI staining, and flow cytometry assays. In vivo assays were conducted to further verify the role of ALOX15 and its metabolite in lung cancer. We found that ALOX15 expression was upregulated in lung cancer patients after 5-FU treatment. ALOX15 mediated the release of 15-HETE, driving lung cancer cells to ferroptosis. Moreover, ALOX15-mediated accumulation of 15-HETE stimulated anti-tumor CD8 + T cell immunity in vivo and in vitro. Mechanistically, ALOX15 upregulated TCF1, promoting the stem-like behaviors of CD8 + T cells. Moreover, upregulated TCF1 suppressed the expression of immune checkpoint genes. ALOX15 functions as an anti-tumor gene in lung cancer. TCF1-mediated 15-HETE uptake drives lung cancer cell ferroptosis and long-existing of CD8 + T cells. Therefore, ALOX15 may be a potential target for lung cancer.