Fatty acids in tumor-derived exosomes induce a metabolic switch resulting in immune dysfunction in dendritic cells. Dendritic cells (DCs) are central regulators of antitumor immunity but are often suppressed within tumors. This results in poor T cell activation and limits the efficacy of checkpoint blockade therapy, which aims to reactivate antitumor immunity. Defining the factors that induce DC dysfunction within the immunosuppressive tumor microenvironment is therefore expected to enable improved outcomes after immunotherapy. One such proposed factor is the release of exosomes by tumor cells. Exosomes are extracellular vesicles that contain distinct components of the cells that secrete them and are important mediators of intercellular crosstalk. Tumor-derived exosomes (TDEs) are of particular interest, because the nucleotides, proteins, metabolites, and lipids they contain can suppress antitumor immunity. Yin et al. aimed to unravel the effect of TDEs on immunity with a focus on TDE-derived lipids. First, they demonstrated that TDEs not only induce lipid accumulation in DCs but also negatively affect their function in vitro. TDE-exposed DCs expressed more inhibitory checkpoint proteins and suppressive cytokines, were less capable of activating antitumor CD8+ T cells, and induced generation of immunosuppressive regulatory T cells. Next, they generated fluorescently labeled TC-1 cervical cancer cells that secrete traceable TDEs to demonstrate that TDEs were mainly captured by lipid-rich dysfunctional DCs within the tumor microenvironment in vivo. Lipidomic analysis of TDEs in comparison with non-cancer cell-derived exosomes revealed that the former contained fatty acids that directly induce lipid accumulation and immune dysfunction in DCs. Further transcriptomic analysis revealed that TDE-treated DCs displayed enriched expression of lipid metabolism genes. In particular, they were enriched for downstream targets of the ligand-activated transcription factor peroxisome proliferator-activated receptor α (PPARα). Using PPARα-knockout mice, the authors demonstrated that PPARα deficiency resulted in decreased DC lipid content and improved CD8+ T cell function, resulting in slower tumor growth in the MC38 colon carcinoma mouse model. Combination therapy of PPARα and immune checkpoint inhibition further inhibited MC38 tumor growth and improved survival. Mechanistically, the authors demonstrated that fatty acids within TDEs induced a switch from glycolysis toward mitochondrial fatty acid oxidation. Yet the molecular mechanisms by which this metabolic shift inhibits DC function remain to be investigated. An important future line of investigation is whether the observed TDE-induced metabolic changes and immune dysfunction are also at play in human tumor-infiltrating DCs. This is especially important from a translational perspective because it could help to predict response or resistance to checkpoint inhibition in the clinic and could pave the way to better designed combination immunotherapies.