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 CD8T 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 CD8T 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.

中文翻译：

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释放免疫疗法的力量：质粒 IL-15 和吉西他滨的组合递送以协同重塑肿瘤微环境

近年来，癌症免疫疗法已成为一种有前景的临床治疗策略。不幸的是，免疫疗法令人满意的抗肿瘤治疗效果受到复杂的免疫抑制肿瘤微环境（ITM）的限制。为了重塑 ITM 并减轻免疫逃避，我们构建了 FA-PEG 修饰的脂质体来分别递送质粒 IL-15 (pIL-15) 和吉西他滨 (GEM) (FPCL@pIL-15 + FPGL)。 FPCL@pIL-15 (150 nm) 和 FPGL (120 nm) 表现出对称的球形结构，以及依赖叶酸 (FA) 专门靶向功能在肿瘤组织上的理想渗透和积累。 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 CD8T 细胞的增殖和共激活。 FPGL上调自然杀伤组2成员D配体（NKG2DL）的表达并增强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）效应促进CD8T细胞的激活。更重要的是，联合给药在皮下4T1肿瘤模型中达到了预期的抗肿瘤功效。从本质上讲，我们证明了 FPCL@pIL-15 与 FPGL 的结合可以协同刺激和动员免疫系统来逆转 ITM 并触发抗肿瘤免疫反应，这表明在免疫治疗中具有巨大的应用潜力。