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

Abstract

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.

Radiotherapy-Driven Nanoprobes Targeting for Visualizing Tumor Infiltration Dynamics and Inducing Ferroptosis in Myeloid-Derived Suppressor Cells

“…The engineering of Fe 3 O 4 -αPD-L1 nanoprobes involves the modification of oil-soluble Fe 3 O 4 nanoparticles with bis-phosphonic acid and maleimide modified polyethylene glycol (DP-PEG-Mal) to confer hydrophilicity and enhanced modifiability . The modified Fe 3 O 4 nanoparticles were then conjugated with an anti-PD-L1 antibody (αPD-L1) through the interaction between the terminal maleimide functional group and cysteine sulfhydryl group on αPD-L1 to achieve the final Fe 3 O 4 -αPD-L1 nanoprobes.…”

“…Specifically, compared with the control group, 7, 24, and 22 proteins related to ROS elevation were identified in the Fe 3 O 4 -αPD-L1, IR, and IR + Fe 3 O 4 -αPD-L1 groups, respectively, indicating the induction of ROS production by Fe 3 O 4 -αPD-L1, IR, and IR + Fe 3 O 4 -αPD-L1. ROS have been demonstrated to induce lipid peroxidation in cells, leading to ferroptosis. , This process is associated with a down-regulation in the protein expression of glutathione and its synthetic precursors, glutamate and cysteine, indicating an imbalance between the antioxidant system and increased ROS production . Changes in mitochondrial morphology and function are key characteristics of ferroptosis .…”

“…This process induces lipid peroxidation, disrupting cellular redox homeostasis and ultimately culminating in ferroptosis . While numerous ferroptosis inducers have demonstrated effectiveness in killing tumor cells, their impact on immune cells, particularly MDSCs, remains poorly understood. Two pioneered studies have shed light on this topic, yet reveal contrasting findings.…”

A Mannose-Modified Lipid Calcium Phosphate Nanoparticle Vaccine Increased the Anti-Tumor Immune Response by Modulating the Tumor Microenvironment

“…By modulating the tumor microenvironment, this vaccine can significantly enhance the anti-tumor immune response, providing new possibilities for tumor treatment. Several studies [202][203][204][205] have explored the treatment of this nanoparticle nucleic acid vaccine through clinical trials. These clinical trials typically involve the treatment of tumor patients in groups, with one group receiving the mannose-modified lipid calcium phosphate nanoparticle vaccine and the other group acting as a control group receiving either standard treatment or a placebo.…”

Radioactive Hydroxyapatite Microspheres Empower Sustainable In Situ Tumor Vaccination

“…Additionally, some materials with imaging capabilities can track the fate of vaccines in vivo . Recently, a strategy using magnetic iron oxide nanoadjuvants has been developed to capture antigens in situ , allowing for the visualization of radiotherapy-induced ISV through magnetic resonance imaging . However, the success of current strategies for antigen release heavily relies on the dose and accuracy of external beam radiation .…”