Successful dendritic cell vaccines require lasting in-situ TNFa secretion to license antitumor CD8 ⁺ T cell cytotoxicity

Dendritic cells (DCs) are central to activating cytotoxic CD8⁺ T cells, yet DC-based vaccines have achieved limited success against established tumors. To address this gap, we analyzed the transcriptomic and functional changes CD8⁺ T cells undergo following interactions with DC subsets in lymphoid organs and tumor sites. This approach allowed us to map their trajectory from naïve to fully cytotoxic effector cells. We found that classical DCs in lymphoid organs provide essential antigen presentation but fail to elicit cytotoxicity. Instead, antigenexperienced CD8⁺ T cells require additional inflammatory signals, primarily through TNFα, delivered at tumor sites by infiltrating myeloid DCs. Effective cytotoxic responses therefore depend on the synchronization of these distinct, temporally separated signals. Notably, tumor antigen–pulsed DC vaccines rapidly lose TNFα expression after infiltrating tumors, limiting their efficacy. These findings establish a sequential model of T cell activation and suggest strategies to enhance the potency of DC-based immunotherapies.