溶瘤病毒在实体瘤免疫治疗中的应用及免疫微环境调节机制

Application of Oncolytic Viruses in Immunotherapy of Solid Tumors and Regulatory Mechanisms of Immune Microenvironment

摘要: 实体瘤高度免疫抑制的肿瘤微环境(Tumor Microenvironment, TME)是介导肿瘤免疫逃逸、降低放化疗及免疫治疗临床应答的关键瓶颈。溶瘤病毒(Oncolytic Viruses, OVs)能够特异性靶向裂解肿瘤细胞，同时多重调控抑制性TME，是实体瘤免疫治疗领域极具转化价值的新型生物制剂。本文系统梳理OVs重塑实体瘤免疫微环境的核心作用机制：通过诱导免疫原性细胞死亡释放危险相关分子模式与病原体相关分子模式，启动初始抗肿瘤免疫应答；调控免疫细胞、细胞因子及趋化因子网络，逆转免疫细胞失衡格局；降解致密细胞外基质、修复紊乱肿瘤血管，解除免疫细胞浸润物理屏障。现有临床数据表明，单药OVs安全性良好，但整体抗肿瘤有效率偏低；与免疫检查点抑制剂、肿瘤疫苗、过继性T细胞疗法、靶向药物及放化疗联合应用可形成显著协同效应，在黑色素瘤、肝癌、肺癌、胰腺癌等实体瘤中明显提升客观缓解率与患者生存获益。现阶段OVs临床转化仍面临全身递送效率低下、机体抗病毒免疫清除病毒、脱靶毒性、标准化治疗方案缺失、规模化制备成本高昂等多重挑战。依托基因工程修饰、纳米递送系统、精准介入给药等技术革新，有望进一步增强OVs肿瘤靶向性、溶瘤活性与免疫激活能力，突破现有应用壁垒，推动OVs成为实体瘤综合免疫治疗的核心手段，为晚期实体瘤患者提供高效、低毒的新型治疗策略。

Abstract: The highly immunosuppressive tumor microenvironment (TME) of solid tumors constitutes a critical bottleneck that mediates tumor immune evasion and attenuates clinical responses to radiotherapy, chemotherapy and immunotherapy. Oncolytic viruses (OVs), a novel class of biological agents with prominent translational value for solid tumor immunotherapy, can specifically target and lyse tumor cells while exerting multifaceted regulation on the suppressive TME. This paper systematically summarizes the core mechanisms by which OVs remodel the immune microenvironment of solid tumors: triggering primary anti-tumor immune responses by inducing immunogenic cell death to release damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs); reversing the imbalance of immune cell populations via modulating the network of immune cells, cytokines and chemokines; and removing physical barriers to immune cell infiltration through degrading dense extracellular matrix and restoring dysfunctional tumor vasculature. Current clinical data demonstrate that monotherapy with OVs exhibits favorable safety profiles yet modest overall anti-tumor response rates. Combinatorial regimens pairing OVs with immune checkpoint inhibitors, tumor vaccines, adoptive T cell therapy, targeted agents, radiotherapy or chemotherapy yield prominent synergistic effects, significantly elevating objective response rates and survival benefits for patients with solid tumors including melanoma, hepatocellular carcinoma, lung cancer and pancreatic cancer. The clinical translation of OVs currently faces multiple obstacles, such as inefficient systemic delivery, viral clearance by host antiviral immunity, off-target toxicity, lack of standardized therapeutic protocols and high costs of large-scale production. Technological innovations including genetic engineering modification, nano-delivery systems and precise interventional administration are expected to further enhance the tumor tropism, oncolytic activity and immune-stimulating capacity of OVs, break through existing application limitations, advance OVs as a core component of comprehensive immunotherapy for solid tumors, and provide a novel high-efficacy, low-toxicity therapeutic strategy for patients with advanced solid tumors.