Abstract 5762: Engineering cell membrane nanoparticlesenhance immunotherapy and radiodynamic therapy for lung adenocarcinoma by promoting cGAS-STING and ferroptosis

Abstract Background: Immunotherapy is a promising approach for lung cancer, but its effectiveness is limited by tumor heterogeneity. Nanoparticle-based targeted drug delivery systems offer advantages such as targeted drug-loading capacity, and hypotoxicity, showing great potential in improving therapeutic efficacy. This study introduces a targeted drug delivery strategy based on immune-activating nanoparticles that achieves precise drugs delivery in tumor areas. Consequently, this approach remodels the microenvironment and induces tumor cytotoxicity. Method: In this study, we first constructed a targeted nanoparticle delivery system FP@CC. The vehicle utilized lung adenocarcinoma cell membranes as the outer shell and encapsulated iron-platinum nanoparticles and STING agonist Vadimezan. Then, TREM2 antibodies were conjugated on the outer layer. The structure of FP@CC-aT2 was characterized by HADDF-STEM and its safety was evaluated by hemolysis test. In vitro, its ability to induce death was verified by AM/PI staining, and to induce ferroptosis was detected by C11 assay. Furthermore, we evaluated its antitumor effects in subcutaneous tumor models. The composition of immune cells within the tumor microenvironment was analyzed using flow cytometry. Results: We initially performed HADDF-STEM analysis on the nanoparticle precursor FP/Vad@CC, revealing its uniform sphericity. For security, no significant hemolysis was observed at different concentrations of FP/Vad@CC. Then, the structures of FP/Vad@CC-aT2 and FP/Vad@CC are relatively stable (Fig 1).The number of dead cells significantly increased after deal with FP@CC, and the effect was significantly enhanced when combined with X-ray. Moreover, C11, utilizing to assess the changes in intracellular reactive oxygen species (ROS), found that FP@CC led to a significant increase in ROS, comparable to induction by H2O2. Both could be effectively prevented by ferroptosis inhibitor(Fig 2).In vivo, FP/Vad@CC-aT2 was applied to a subcutaneous tumor model in C57. It exhibited excellent therapeutic efficacy and biocompatibility. Flow cytometry revealed that FP/Vad@CC-aT2 had the anticipated impact on macrophages within the tumor: a significant reduction in CD11high/CD206high cells and opposite in the ratio of M1/M2-like macrophages (Fig 3). Conclusion: This study developed a targeted drug delivery strategy, FP/Vad@CC-aT2, to improve the tumor microenvironment (TME). We conducted preliminary experiments in vitro and in vivo to validate its physicochemical properties and tumor inhibitory effects, including the induction of ferroptosis. We assessed its safety in mouse and obtained initial evidence of FP/Vad@CC-aT2's ability to remodel the subtypes of macrophage.Moving forward, we will validate its therapeutic and impact on the TME after surgical procedures. Citation Format: Haiyu Zhou, Hongrui Qiu, Shiying Li, Bin Xu, Shengbo Liu, Huili Wang, Hengliang Hou. Engineering cell membrane nanoparticlesenhance immunotherapy and radiodynamic therapy for lung adenocarcinoma by promoting cGAS-STING and ferroptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5762.