Oxygen self-supplying nanoradiosensitizer activates cGAS-STING pathway to enhance radioimmunotherapy of triple negative breast cancer.

Radiotherapy (RT)-mediated immune activation is insufficient for effective therapy of triple-negative breast cancer (TNBC) due to the immunosuppressive tumor microenvironment. Herein, we developed an oxygen self-supplying nanoradiosensitizer to activate immunogenic cell death (ICD) and the cGAS-STING signaling pathway, elevating the anti-tumor immune response and improving radioimmunotherapy for TNBC. The nanoradiosensitizer was fabricated using astragaloside liposome-encapsulated FePt alloy and MnO nanocrystals (ALFM). The ALFM targeted the glucose transporter-1 (GLUT-1) receptor in TNBC and effectively entered tumor cells. Subsequently, the ALFM responded to the weakly acidic tumor microenvironment and degraded, releasing FePt and Mn2+ ions. The released Mn2+ ions not only elevated cellular ROS levels via a Fenton-like reaction but also activated the cGAS-STING signaling pathway, which stimulated the anti-tumor immune response. In addition, the FePt alloy catalyzed a cascade reaction, producing ROS and O2 in tumor cells, alleviating tumor hypoxia, and enhancing the RT effect. Besides, ROS-mediated cell damage induced the ICD effect in TNBC, promoted dendritic cell maturation and the infiltration of cytotoxic T lymphocytes, ultimately eliciting cancer immunotherapy. In vivo experimental results demonstrated that ALFM effectively activated the antitumor immune response and improved the radioimmunotherapy effect for TNBC. Overall, this work presents an effective strategy for enhanced radioimmunotherapy of TNBC.

Wang X ，Yang Y ，Wang P ，Li Q ，Gao W ，Sun Y ，Tian G ，Zhang G ，Xiao J ... -  《-》

Multifunctional nanocomposites utilizing ruthenium (II) complex/manganese (IV) dioxide nanoparticle for synergistic reinforcing radioimmunotherapy.

Radiotherapy (RT) stands as a frontline treatment modality in clinical breast oncology, yet challenges like ROS reduction, high toxicity, non-selectivity, and hypoxia hinder efficacy. Additionally, RT administered at different doses can induce varying degrees of radioimmunotherapy. High doses of radiation (>10 Gy) may result in immune suppression, while moderate doses (4-10 Gy), although capable of mitigating the immune suppression caused by high-dose radiation, are often insufficient in effectively killing tumor cells. Therefore, enhancing the generation of ROS and ameliorating the tumor hypoxic immune-suppressive microenvironment at moderate radiation doses could potentially drive radiation-induced immune responses, offering a fundamental solution to the limitations of RT. In this study, a novel multifunctional nanoplatform, RMLF, integrating a Ru (II) complex into folate-functionalized liposomes with BSA-MnO2 nanoparticles was proposed. Orthogonal experimental optimization enhances radiosensitization via increasing accumulation in cancer cells, elevating ROS, and contributing to a dual enhancement of the cGAS-STING-dependent type I IFN signaling pathway, aimed to overcome the insufficient DAMPs typically seen in the conventional RT at 4 Gy. Such a strategy effectively activated cytotoxic T lymphocytes for infiltration into tumor tissues and promoted the polarization of tumor-associated macrophages from the M2 to M1 phenotype, substantially bolstering immune memory responses. This pioneering approach represents the first use of a ruthenium complex in radioimmunotherapy, activating the cGAS-STING pathway to amplify immune responses, overcome RT resistance, and extend immunotherapeutic potential.

Peng J ，Quan DL ，Yang G ，Wei LT ，Yang Z ，Dong ZY ，Zou YM ，Hou YK ，Chen JX ，Lv L ，Sun B ... -  《JOURNAL OF NANOBIOTECHNOLOGY》

A multifunctional cascade gas-nanoreactor with MnO(2) as a gatekeeper to enhance starvation therapy and provoke antitumor immune response.

Glucose oxidase (GOx)-mediated starvation therapy is an effective tumor treatment that blocks energy and activates the immune response. However, the insufficient tumor immunogenicity and immunosuppressive tumor microenvironment (TME) limited its therapeutic efficacy. To address this, we have designed a multifunctional cascade gas-nanoreactor with a MnO2 coating, which serves as an out gatekeeper to encapsulate both GOx and a carbon monoxide (CO) donor (denoted as GCM). Due to the protective effect of MnO2 coating, GCM maintains better stability in normal physiological environments, enhancing the catalytic activity of GOx and minimizing toxic side effects. Upon accumulation in the tumor, the degradation of MnO2 coating exposes the GOx enzyme, thereby initiating a cascade catalysis reaction to generate hydrogen peroxide (H2O2) and release CO in the hypoxic conditions. Additionally, the released Mn2+ reacts with H2O2 to generate toxic hydroxyl radical (•OH) as chemodynamic therapy (CDT). The synergistic treatments of starvation therapy, CO gas therapy and CDT effectively kill cancer cells and amplify immunogenic cell death (ICD), maturing DC cells and activating anti-tumor immune response. Furthermore, the released CO increases M1 macrophages infiltration and reduces myeloid-derived suppressor cells (MDSCs) infiltration, thus reversing the immunosuppressive TME. This multifunctional gas-nanoreactor provides a strategy for CO gas generation to trigger a robust anti-tumor immune response and has the potential for clinical application in cancer immunotherapy. STATEMENT OF SIGNIFICANCE: A multifunctional cascade gas-nanoreactor with a MnO2 gatekeeper was developed to perform synergistic treatments involving starvation therapy, CO gas therapy and chemodynamic therapy (CDT) for tumor elimination. The MnO2 gatekeeper enhanced the catalytic activity of GOx within the nanoreactor by generating oxygen, thereby minimizing toxic side effects after intravenous injection. The gas-nanoreactor amplified ICD through synergistic treatments to mature DC cells and activate anti-tumor immune response. Furthermore, the released CO could reverse the immunosuppression of the TME to enhance cancer immunotherapy. The combination strategy utilizing the gas-nanoreactor demonstrates clinical potential for facilitating cancer immunotherapy.

Ren H ，Bai Y ，Liu Z ，Ma C ，Tao X ，Wang Q ，Lian H ，Li X ... -  《-》

Radiation-activated PD-L1 aptamer-functionalized nanoradiosensitizer to potentiate antitumor immunity in combined radioimmunotherapy and photothermal therapy.

Chen B ，He Y ，Bai L ，Pan S ，Wang Y ，Mu M ，Fan R ，Han B ，Huber PE ，Zou B ，Guo G ... -  《-》

Synergizing autophagic cell death and oxaliplatin-induced immunogenic death by a self-delivery micelle for enhanced tumor immunotherapy.

Chemotherapy has become an emerging strategy to activate cytotoxic T cell responses by inducing immunogenic cell death (ICD), but the level of antitumor immunity induced by chemotherapeutic agents, such as oxaliplatin (OXA), is limited due to inadequate tumor antigen presentation and T cell activation. Inducing autophagic cell death (ACD) promotes the release of tumor antigen and the recruitment of dendritic cells, therefore strengthening antitumor immune responses. Here we simultaneously activate ICD and ACD with tumor targeting micelle to achieve enhanced antitumor chemo-immunotherapy. A self-delivery micelle is formulated by conjugating OXA prodrug with tocopherol succinate (TOS) as a hydrophobic segment and further encapsulates autophagy activator SMER28 to afford TOPR/SMER28, which specifically targets αvβ3 on tumor cells with c(RGDfK). Upon cellular internalization, OXA is released from the prodrug in response to the high concentration of reduced glutathione (GSH) in tumor cells, triggering ICD and releasing associated molecular patterns (DAMPs) signaling molecules to stimulate immunity. Meanwhile, SMER28 over-activates autophagy to induce autophagic cell death, which further leads to the maturation of dendritic cells and ultimately activates anti-tumor immune response. In the 4T1 tumor-bearing mice, the combination of OXA and SMER28 effectively inhibits tumor growth and activates antitumor immune responses. The tumor targeted micelle releases OXA and SMER28 in an on-demand profile and strengthens tumor chemo-immunotherapy by synergizing ICD and ACD, providing an alternative for antitumor immunotherapy. STATEMENT OF SIGNIFICANCE: Chemotherapy induces immunogenic cell death (ICD) to activate anti-tumor immunity. However, the efficacy is limited by low levels of antigen presentation and T cell activation. To strengthen the antitumor immune responses induced by ICD, we first combine autophagic cell death (ACD) with ICD by formulating a glutathione-responsive oxaliplatin prodrug micelle co-encapsulating the autophagy activator SMER28. The activated autophagic level by SMER28 enhances the release of antigen and the recruitment of APCs, and ultimately bolsters T cell-mediated antitumor immune responses. We provide a potential strategy to amplify antitumor immune effects by combining autophagy activation with chemotherapy.

Deng T ，Chen D ，Chen F ，Xu C ，Zhang Q ，Li M ，Wang Y ，He Z ，Li M ，He Q ... -  《-》