Immunogenic Radiation Therapy for Enhanced Antitumor Immunity via a Core–Shell Nanosensitizer-Mediated Immunosuppressive Tumor Microenvironment Modulation

Abstract

Due to the immunosuppressive tumor microenvironment (TME) and weak radiation absorption, the immune response triggered by radiation therapy (RT) is limited. Herein, a core−shell nanosensitizer UiO@MnS (denoted as UM) was genuinely constructed for the amplification of RT efficacy and induction of immunogenicity via integrating MnS-reprogrammed TME with Hf-based UiOsensitized RT. The acid-sensitive MnS would produce H 2 S under acidic TME to improve oxygenation through inhibition mitochondrial respiration and reducing metabolic oxygen consumption, leading to decreased HIF-1α expression and enhanced radiosensitization. In addition, the generated H 2 S inhibited the catalase activity to increase the H 2 O 2 level, which subsequently enhanced the Mn 2+ -mediated Fenton-like reaction, resulting in G2/M cell cycle arrest to improve the cellular sensitivity for radiation. This impressive tumor oxygenation, cell cycle arrest, and radiosensitization procedure boosted RT efficacy and resulted in strong antitumor immunogenicity. Taken together, combining the immunosuppressive TME modulation with a sensitizing radiation strategy shows great promise for magnifying immunogenic RT outputs.

[FeIIICl(TMPPH2)][FeIIICl4]2: A Stand-Alone Molecular Nanomedicine That Induces High Cytotoxicity by Ferroptosis

“…It can be seen from Figure 1 e that Fe-TMPP produced considerable •OH in a concentration-dependent manner upon incubating with H 2 O 2 over 3 h. The generation of •OH was confirmed by electron paramagnetic resonance (EPR) spectroscopy, using DMPO as the spin trap. As shown in Figure 1 f, the EPR spectrum of Fe-TMPP gave rise to a strong four-line signal with a 1:2:2:1 peak-to-peak intensity pattern, characteristic of the generation of •OH from H 2 O 2 [ 4 , 5 ].…”

“…Molecules 2024, 29, x FOR PEER REVIEW 6 of 14 to a strong four-line signal with a 1:2:2:1 peak-to-peak intensity pattern, characteristic of the generation of •OH from H2O2 [4,5]. Fe-TMPP is supported by a porphyrin-based ligand, which is often used for type II PDT of cancer [3,7,37].…”

“…Materials designed to target the unique features of the tumor microenvironment (TME), such as the over-expression of H 2 O 2 and glutathione (GSH), weak acidity, hypoxia, and immunosuppression, are attracting intensive interest in the field of nanomedicine [ 1 , 2 , 3 , 4 , 5 , 6 ]. Materials that are responsive exclusively to the TME imply low systemic toxicity and thus fewer side effects.…”

Janus ACSP Nanoparticle for Synergistic Chemodynamic Therapy and Radiosensitization

“…In this article, we developed an integrated Janus Au–Cu 2– x Se nanoparticle (NP) for tuning the cell cycle into a radiosensitive one, synergistic CDT and RT, regulating the DNA damage repair signal pathway, and computed tomography (CT) imaging (Scheme ). After the accumulation of Au–Cu 2– x Se NPs in the tumor region, the NPs induce a Fenton-like reaction and generate •OH stress, , leading to cell cycle arrest. During the X-ray irradiation, the Au serves as a radiosensitizer, enhancing intracellular radiation deposition and producing substantial amounts of high-energy electrons and •OH, while the Cu + Fenton-like reaction is accelerated, realizing synergistic CDT and RT.…”

[Fe^IIICl(TMPPH₂)][Fe^IIICl₄]₂: A Stand-Alone Molecular Nanomedicine that Induces High Cytotoxicity by Ferroptosis

“…Materials designed to target the unique features of the tumor microenvironment (TME), such as the over-expression of H2O2 and glutathione (GSH), weak acidity, hypoxia, and immunosuppression, are attracting intensive interest in the field of nanomedicine. [1][2][3][4][5][6] On the one hand, materials that are responsive exclusively to the TME imply low systemic toxicity and thus fewer side effects. On the other hand, disturbing the complex homeostasis of the TME may result in effective cancer therapy by novel cell death modalities (e.g., ferroptosis, pyroptosis, and immunogenic cell death), [7][8][9] and the resensitization of cells to conventional therapies.…”