减毒弓形虫在肿瘤免疫治疗中的应用与 机制研究进展

Research Progress on the Application and Mechanism of Attenuated Toxoplasma gondii in Tumor Immunotherapy

摘要: 肿瘤免疫治疗在血液肿瘤中取得显著进展，但实体瘤仍面临“冷肿瘤”免疫抑制微环境导致疗效受限的关键瓶颈。近年来，基于病原微生物的免疫激活策略为肿瘤治疗提供了新的思路，其中减毒弓形虫因其独特的免疫调控能力成为研究热点。本文系统综述了减毒弓形虫在肿瘤免疫治疗中的生物学基础、构建策略及抗肿瘤作用机制。弓形虫通过其生命周期阶段转换及ROP、GRA等效应蛋白精细调控宿主信号通路，天然诱导以Th1型为核心的免疫应答，为其减毒利用提供了理论依据。在减毒策略方面，基因工程减毒(如尿嘧啶营养缺陷型CPSII、OMPDC突变株及毒力/效应蛋白基因敲除)已成为主流方法，可在降低毒力的同时保留甚至增强免疫原性；物理减毒作为补充手段亦展现一定应用潜力。在抗肿瘤机制上，减毒弓形虫可通过激活Th1型免疫反应、促进树突状细胞抗原递呈、增强CD8⁺ T细胞浸润、重塑免疫抑制性肿瘤微环境，并通过分泌效应蛋白直接调控肿瘤细胞增殖、迁移及凋亡等多途径发挥作用，在多种实体瘤模型中表现出广谱抗肿瘤活性。此外，其与免疫检查点抑制剂等疗法联合应用显示出协同增效潜力。尽管如此，减毒弓形虫的临床转化仍面临安全性、可控性及长期免疫影响等挑战。未来需进一步优化减毒设计、解析关键分子机制并建立系统性风险评估体系，以推动其向临床应用发展。

Abstract: Tumor immunotherapy has made significant progress in hematological malignancies, but solid tumors still face the key bottleneck of limited efficacy due to the “cold tumor” immunosuppressive microenvironment. In recent years, the immune activation strategy based on pathogenic microorganisms has provided new ideas for tumor treatment. Among them, attenuated Toxoplasma gondii has become a research hotspot due to its unique immune regulation ability. This article systematically reviews the biological basis, construction strategy and anti-tumor mechanism of attenuated Toxoplasma gondii in tumor immunotherapy. Toxoplasma gondii regulates the host signaling pathway through its life cycle phase transition and effector proteins such as ROP and GRA, and naturally induces an immune response centered on Th1 type, which provides a theoretical basis for its attenuated utilization. In terms of attenuation strategies, genetic engineering attenuation (such as uracil auxotroph CPSII, OMPDC mutants and virulence/effector protein gene knockout) has become the mainstream method, which can reduce virulence while retaining or even enhancing immunogenicity; physical attenuation as a supplementary means also shows certain application potential. In the anti-tumor mechanism, attenuated T. gondii can play a role by activating Th1 immune response, promoting dendritic cell antigen presentation, enhancing CD8⁺ T cell infiltration, remodeling immunosuppressive tumor microenvironment, and directly regulating tumor cell proliferation, migration and apoptosis by secreting effector proteins, showing broad-spectrum anti-tumor activity in a variety of solid tumor models. In addition, its combination with therapies such as immune checkpoint inhibitors shows synergistic potential. However, the clinical transformation of attenuated T. gondii still faces challenges such as safety, controllability, and long-term immune effects. In the future, it is necessary to further optimize the attenuated design, analyze the key molecular mechanisms and establish a systematic risk assessment system to promote its clinical application.