Orchestrating intratumoral DC-T cell immunity for enhanced tumor control via radiotherapy-activated TLR7/8 prodrugs in mice

Optimizing intratumoral dendritic cell (DC)-T cell responses is pivotal for effective cancer immunotherapy. However, the mechanistic governing these dynamics within the tumor microenvironment (TME) remains unclear, and strategies to improve their therapeutic potential are underexplored. Here, we show that precise radiotherapy activates the pro-TLR7/8 agonist imidazoquinoline (IMDQ) locally in preclinical tumor models, stimulating DCs to elicit T cell immunity without the need for further recruitment or causing systemic toxicity. Mechanistically, this synergistic approach triggers type I interferon via STING and MyD88 signaling pathways, strengthening local immune responses. Importantly, we reveal that fractionated, low-dose radiotherapy can effectively optimize local DC-T cell dynamics to control the irradiated tumor, while also promoting abscopal effect. Thus, our findings underscore the critical role of harnessing intratumoral DCs to reinvigorate pre-existing T cell immunity and provide mechanistic insights into improving both local and distal tumor control, opening new avenues for advancing cancer immunotherapy. Systemic administration of TRL7/8 agonists enhances anti-tumor immunity by enhancing dendritic cell (DC) activation, but also causes systemic toxicity. Here, the authors show that, in tumor mouse models, a radiotherapy-activated, N-oxide imidazoquinoline prodrug promotes controlled, local activation of intratumoral DC-T cell dynamics, while promoting systemic anti-tumor responses.