弓形虫感染对肿瘤发生发展的双重作用 研究进展

Research Progress on the Dual Effects of Toxoplasma gondii Infection on Tumorigenesis and Development

摘要: 弓形虫是一种全球分布的专性细胞内寄生原虫，约三分之一人口呈潜伏感染状态。急性感染后，弓形虫以组织包囊形式在宿主体内持续存在，这种长期寄生状态为弓形虫与肿瘤的相互作用提供了生物学基础。流行病学证据表明，癌症患者弓形虫血清阳性率高于健康人群，荟萃分析显示总体感染风险约为对照组的3倍，脑肿瘤风险增加约2倍，儿童血液肿瘤患者感染风险比值比达到6。然而，上述关联面临选择偏倚、测量偏倚、残余混杂及反向因果等重大方法学挑战，双向孟德尔随机化研究甚至提示脑肿瘤遗传易感性可能反向增加感染风险，因此“弓形虫慢性感染致癌”假说远未得到证实。机制研究揭示，慢性感染通过诱导持续炎症、重塑肿瘤微环境、削弱免疫监视促进肿瘤发生。在急性感染阶段，弓形虫激活Th1型免疫应答，上调IL-12和IFN-γ，促进CD8阳性T细胞和自然杀伤(NK)细胞浸润，抑制实体瘤生长。基于此开发的减毒活虫株和非活体成分在乳腺癌、黑色素瘤、胰腺癌等小鼠模型中取得抑瘤效果，与PD-1和PD-L1抑制剂联用产生协同效应。本文在综述上述进展的基础上，着重对流行病学证据的方法学质量进行批判性分析，并深入解读双向孟德尔随机化研究对因果关系推断的颠覆性意义。目前研究仍面临挑战，急慢性感染阶段难以区分，临床转化路径不明确，未来需前瞻性队列研究与转化研究并行推进。

Abstract: Toxoplasma gondii is a globally distributed obligate intracellular parasite, and about one-third of the population is latently infected. After acute infection, T. gondii persists in the host in the form of tissue cysts. This long-term parasitic state provides a biological basis for the interaction between T. gondii and tumors. Epidemiological evidence shows that the serum positive rate of Toxoplasma gondii in cancer patients is higher than that in healthy people. Meta-analysis shows that the overall risk of infection is about 3 times that of the control group, the risk of brain tumors is about 2 times higher, and the odds ratio of infection risk in children with hematological tumors is 6. However, the above association faces major methodological challenges such as selection bias, measurement bias, residual confounding, and reverse causality. Bidirectional Mendelian randomization studies have even suggested that genetic susceptibility to brain tumors may reversely increase the risk of infection. Therefore, the “carcinogenicity of chronic infection of Toxoplasma gondii” hypothesis is far from confirmed. Mechanism studies have revealed that chronic infection promotes tumorigenesis by inducing persistent inflammation, remodeling tumor microenvironment, and weakening immune surveillance. In the acute infection stage, T. gondii activates Th1 type immune response, up-regulates IL-12 and IFN-γ, promotes the infiltration of CD8 positive T cells and natural killer (NK) cells, and inhibits the growth of solid tumors. The attenuated live strains and non-living components developed based on this have achieved anti-tumor effects in mouse models such as breast cancer, melanoma, and pancreatic cancer, and have synergistic effects with PD-1 and PD-L1 inhibitors. On the basis of summarizing the above progress, this paper focuses on the critical analysis of the methodological quality of epidemiological evidence, and deeply interprets the subversive significance of two-way Mendelian randomization research on causality inference. At present, the research still faces challenges, the acute and chronic infection stages are difficult to distinguish, and the clinical transformation path is not clear. In the future, prospective cohort studies and transformation studies need to be promoted in parallel.