Abstract：
Cancer immunotherapy has emerged as a promising clinical treatment strategy in recent years. Unfortunately, the satisfactory antitumor therapeutic efficacy of immunotherapy is limited by intricate immunosuppressive tumor microenvironment (ITM). To remodel the ITM and alleviate the immune evasion, we constructed FA-PEG-modified liposomes to deliver plasmid IL-15 (pIL-15) and gemcitabine (GEM) (FPCL@pIL-15 + FPGL), respectively. The FPCL@pIL-15 (150 nm) and FPGL (120 nm) exhibited symmetrically spherical structures as well as desirable penetration and accumulation on tumor tissue depending on folic acid (FA) specialized targeting function. The transfected expression of IL-15 efficiently fosters the proliferation and co-activation of Natural killer (NK) cells and CD8+T cells through binding to IL-15R. FPGL upregulated the expression of Natural killer group 2 member D ligands (NKG2DLs) and reinforced recognition by NK cells to alleviate the immune evasion, and simultaneously promoted activation of CD8+T cells through immunogenic cell death (ICD) effects. More importantly, the combinatorial administration achieved intended anti-tumor efficacy in the subcutaneous 4T1 tumor model. In essence, we demonstrated that combining FPCL@pIL-15 with FPGL synergistically stimulates and mobilizes the immune system to reverse the ITM and trigger an anti-tumor immune response, indicating a tremendous potential for application in immunotherapy.
摘要：
近年来，癌症免疫疗法已成为一种有前途的临床治疗策略。不幸的是,复杂的免疫抑制肿瘤微环境（ITM）限制了免疫治疗的令人满意的抗肿瘤疗效。为了重塑ITM并减轻免疫逃避，我们构建了FA-PEG修饰的脂质体来递送质粒IL-15(pIL-15)和吉西他滨(GEM)(FPCL@pIL-15+FPGL),分别。取决于叶酸(FA)专门的靶向功能,FPCL@pIL-15(150nm)和FPGL(120nm)表现出对称的球形结构以及在肿瘤组织上的期望的渗透和积累。IL-15的转染表达通过与IL-15R结合有效促进自然杀伤(NK)细胞和CD8+T细胞的增殖和共活化。FPGL上调自然杀伤组2成员D配体（NKG2DLs）的表达，增强NK细胞的识别，以减轻免疫逃避，同时通过免疫原性细胞死亡（ICD）作用促进CD8+T细胞的活化。更重要的是,联合给药在皮下4T1肿瘤模型中实现了预期的抗肿瘤功效。实质上,我们证明了FPCL@pIL-15与FPGL的结合协同刺激和动员免疫系统以逆转ITM并触发抗肿瘤免疫反应，表明在免疫疗法中应用的巨大潜力。
