Xu Yan, Zhou Yang, Wang Jiahe
Department of Family Medicine, Shengjing Hospital of China Medical University, Shenyang, China.
Department of Gynecology, Shengjing Hospital of China Medical University, Shenyang, China.
Transl Cancer Res. 2025 Nov 30;14(11):8086-8104. doi: 10.21037/tcr-2025-1591. Epub 2025 Nov 26.
Currently, immune checkpoint inhibitors (ICIs) and other immune-activating strategies represent the main approach to cancer treatment; however, immune resistance in many solid tumors limits the immune therapy response and can cause strong toxic side effects. In solid tumors, the development of effective anti-tumor immune responses is hindered by limited immune cell infiltration and an immunosuppressive tumor microenvironment (TME). To overcome current immunotherapy challenges, we proposed a novel approach providing local and stable treatment levels to activate or revitalize anti-tumor immunity, to achieve the effect of TME infiltration and sustained presence in solid tumors.
Using genetic engineering methods to synergistically activate immunity in the TME, we programmed macrophages to express therapeutic payloads, including interleukin (IL)-12 and the signal regulatory protein alpha-Fragment crystallizable fusion protein (SIRPα-Fc), a CD47 ICI. Co-culture studies were performed to evaluate the effects of the genetically engineered macrophages (GEMs) on the T cells and GEMs themselves . We evaluated the tumor response, cellular response, and cytokine response. The GEMs were administered to a mouse model of tumor-cell transplantation, where they were retained and expressed as lentiviral payloads.
The IL-12 secreted by the GEMs provided effector signals for T cells, thereby enhancing the tumor resident anti-tumor macrophages and CD8T-cell populations. In addition, the secretion of SIRPα-Fc enhanced the phagocytic activity of the macrophages toward tumor cells and promoted their antigen presentation function. The combination therapy of dual proteins produced significant synergistic effects in solid tumor models and further enhanced memory immunity. The GEMs also improved the efficacy of ICIs in the ICI-resistant gene engineering tumor models and demonstrated significant anti-tumor efficacy in the metastasis models.
Our study showed the potential clinical application of GEMs in the treatment of tumors.
目前，免疫检查点抑制剂（ICI）和其他免疫激活策略是癌症治疗的主要方法；然而，许多实体瘤中的免疫抵抗限制了免疫治疗反应，并可能导致强烈的毒副作用。在实体瘤中，有效的抗肿瘤免疫反应的发展受到免疫细胞浸润有限和免疫抑制性肿瘤微环境（TME）的阻碍。为了克服当前免疫治疗的挑战，我们提出了一种新方法，提供局部和稳定的治疗水平以激活或重振抗肿瘤免疫力，从而实现TME浸润并在实体瘤中持续存在的效果。
我们使用基因工程方法在TME中协同激活免疫，对巨噬细胞进行编程以表达治疗性有效载荷，包括白细胞介素（IL）-12和信号调节蛋白α-可结晶片段融合蛋白（SIRPα-Fc），一种CD47 ICI。进行共培养研究以评估基因工程巨噬细胞（GEM）对T细胞和GEM自身的影响。我们评估了肿瘤反应、细胞反应和细胞因子反应。将GEM应用于肿瘤细胞移植小鼠模型，在该模型中它们作为慢病毒有效载荷被保留并表达。
GEM分泌的IL-12为T细胞提供效应信号，从而增强肿瘤驻留的抗肿瘤巨噬细胞和CD8 T细胞群体。此外，SIRPα-Fc的分泌增强了巨噬细胞对肿瘤细胞的吞噬活性并促进了它们的抗原呈递功能。双蛋白联合疗法在实体瘤模型中产生了显著的协同效应，并进一步增强了记忆免疫。GEM还提高了ICI在ICI抗性基因工程肿瘤模型中的疗效，并在转移模型中显示出显著的抗肿瘤疗效。
我们的研究表明GEM在肿瘤治疗中具有潜在的临床应用价值。
