Radiotherapy-Triggered In Situ Tumor Vaccination Boosts Checkpoint Blockaded Immune Response via Antigen-Capturing Nanoadjuvants.

In situ vaccination (ISV) formed with the aid of intratumorally injected adjuvants has shed bright light on enhancing the abscopal therapeutic effects of radiotherapy. However, the limited availability of antigens resulting from the radiotherapy-induced immunogenic cell death largely hampers the clinical outcome of ISV. To maximally utilize the radiotherapy-induced antigen, we herein developed a strategy by capturing the radiotherapy-induced antigen in situ with a nanoadjuvant comprised of CpG-loaded Fe 3 O 4 nanoparticles. The highly efficient click reaction between the maleimide residue on the nanoadjuvant and sulfhydryl group on the antigen maximized the bioavailability of autoantigens and CpG adjuvant in vivo. Importantly, combined immune checkpoint blockade can reverse T cell exhaustion after treatment with radiotherapy-induced ISV, thereby largely suppressing the treated and distant tumor. Mechanistically, metabolomics reveals the intratumorally injected nanoadjuvants disrupt redox homeostasis in the tumor microenvironment, further inducing tumor ferroptosis after radiotherapy. Overall, the current study highlights the immense potential of the innovative antigen-capturing nanoadjuvants for synergistically enhancing the antitumor effect.