Tumoral ALOX5 mediated arachidonic acid metabolism regulates immune response in non-small cell lung cancer.

PURPOSE: Tumor cells reprogram their fatty acid metabolism to meet the demands for their rapid proliferation. However, the interplay between fatty acid metabolism and the tumor microenvironment (TME) in lung cancer remains poorly defined. This study aims to elucidate how arachidonic acid (AA) metabolism, specifically via the enzyme 5-lipoxygenase (ALOX5), modulates anti-tumor immunity in non-small cell lung cancer (NSCLC). METHODS: Data from public transcriptomic datasets were analyzed to identify differentially expressed and immune regulatory fatty acid metabolism-related genes in NSCLC. Spatial correlation between ALOX5 expression and CD8⁺ T cell infiltration was assessed via immunofluorescence. Functional impacts of ALOX5 on tumor growth, immune recruitment, and immunotherapy response were characterized using knockdown and overexpression models. Clinical relevance was evaluated by profiling plasma fatty acids via mass spectrometry in immunotherapy-treated cohorts. RESULTS: Bioinformatic analysis nominated ALOX5-mediatedAA metabolic pathway as a key regulator of immune infiltration. Genetic knockdown of ALOX5 accelerated tumor progression, attenuated CD8⁺ T cell recruitment, and reduced leukotriene B4 (LTB4) production alongside downregulation of cytotoxic (granzymes) and chemotactic genes. Conversely, ALOX5 overexpression suppressed tumor growth and synergized with anti-PD-1 therapy. Exogenous AA supplementation similarly potentiated the efficacy of PD-1 blockade in vivo. Clinically, elevated plasma levels of AA and linoleic acid correlated with improved immunotherapy response and survival outcomes. CONCLUSION: Tumor-intrinsic ALOX5 is a novel tumor suppressor that orchestrates CD8⁺ T infiltration via the AA-LTB4 axis in NSCLC. Our findings establish ALOX5-mediated AA metabolism as a therapeutically targetable pathway to overcome immunotherapy resistance, positioning dietary AA supplementation as a promising adjunctive strategy. CLINICAL TRAIL NUMBER: Not applicable.