铁死亡脂质体增敏免疫疗法应对肿瘤多药耐药的研究

肿瘤多药耐药(MDR)是化疗失败的重要原因，免疫检查点阻断疗法(ICB)治疗耐药肿瘤虽已取得重要进展但临床应用中患者响应率较低，主要原因是患者肿瘤组织树突细胞(DCs)不成熟和T细胞无法浸润。经调研后本项目假设免疫刺激与铁死亡可协同发挥激活DCs、促进细胞因子释放和T细胞增殖及促进T细胞浸润的作用增敏ICB从而高效应对MDR。项目设计了携载CpG ODN的岩藻糖不饱和脂肪酸脂质体，该体系具有癌细胞和DCs双靶向性及肿瘤细胞微环境响应性，可发挥免疫激活与诱发细胞铁死亡两种功能。拟通过研究脂质体的肿瘤微环境应答性、主动靶向性、安全性和稳定性；考察其激活DCs、诱发铁死亡、促进T细胞增殖的表现；评价其与免疫检查点抑制剂PD-L1抗体联用后消除多药耐药肿瘤的能力，揭示多功能脂质体引发免疫激活和铁死亡进而增敏ICB应对肿瘤MDR的机理。本项目对耐药肿瘤的高效精准治疗具有重要意义和临床应用价值。

Multidrug resistance (MDR) is a major obstacle to tumor chemotherapy. Although immune checkpoint blockade therapy (ICB) provides a new weapon against drug-resistant cancer cells and has led to encouraging clinical results via targeting regulatory pathways in T cells to boost the antitumor immunity, a large proportion of cancer patients do not respond well to ICB due to the immature dendritic cells (DCs) and deficient T cell infiltration in tumor tissues. It is hypothesized that the combination of immune stimulation and ferroptosis could synergistically sensitize ICB and inhibit MDR tumors by activating DCs, promoting cytokine release (i.e. TNF-α, IFN-γ) and T cell proliferation and regulating tumor microenvironment to promote T cell infiltration. To verify our hypothesis and potentiate the efficacy of immune stimulation and ferroptosis, a CpG ODN-loaded unsaturated fatty acid liposome which could integrate immune stimulation and ferroptosis into one nano-platform will be developed to facilitate on-demand release of CpG ODN. This liposome will also be surface-engineered with fucose to realize active targeting to both cancer cells and DCs. The tumor microenvironment responsiveness, ability of active targeting, biocompatibility and stability of the liposome will be examined. Then, the performance and synergistic effect on DCs activation, ferroptosis induction, and T cell proliferation will be investigated. Finally, it will be detected whether the liposome activates immune response and improves the efficacy of anti-PD-L1 antibody in doxorubicin resistant breast cancer mouse model. In conclusion, this project will shed light on the mechanism of the integration of immune stimulation and ferroptosis for ICB sensitization. This work is also of great significance and clinical application value for the precise treatment of MDR cancers.