Transcriptomic effects of dietary PUFAs in mouse dendritic cells

The immune system is shaped by the balance of n-3 and n-6 polyunsaturated fatty acids (PUFAs), but how these dietary lipids influence dendritic cells (DCs)— key inducers of adaptive immunity—remains largely unexplored. Importantly, whether an excess of n-6 PUFAs, a hallmark of modern diets, could undermine DC function and immune surveillance remains largely unexplored. Here, we uncover a striking link between dietary lipids and DC dysfunction. We found that an n-6 PUFA-rich diet promotes ferroptosis in DCs via suppression of the Nrf2 antioxidant pathway, impairing their antigen presenting capacity. Accordingly, interventions with dietary n-3 PUFAs or ferroptosis inhibitors reversed these effects, restoring DC function and enhancing responses to DC-based chemo-immunotherapy in a preclinical model of metastatic ovarian cancer. These findings suggest that dietary lipids are not just passive components of metabolism but active regulators of DC function and fate. These findings are critical for the creating novel nutritional interventions that improve vaccination and immunotherapy outcomes. Overall design: Splenic dendritic cells (spDCs) and bone marrow-derived dendritic cells (BMDCs) were isolated from mice fed either an n-6-rich or an n-3-rich diet for 8 weeks for RNAseq profiling