肿瘤细胞治疗研究
英文原题：Oncolytic virotherapy at the tumor microenvironment-CAR Therapy interface: Mechanisms, clinical translation, and future directions.
溶瘤病毒疗法已从一种肿瘤选择性溶细胞策略演变为一种可编程的免疫治疗平台，能够重塑肿瘤微环境（TME）。
溶瘤病毒疗法已从一种肿瘤选择性溶细胞策略演变为一种可编程的免疫治疗平台，能够重塑肿瘤微环境（TME）。溶瘤病毒（OVs）选择性感染恶性细胞，诱导免疫原性细胞死亡，释放肿瘤抗原，并激活固有免疫和适应性免疫，有可能将冷肿瘤转化为炎症状态。然而，临床转化仍受限于抗病毒清除、递送异质性、基质屏障、免疫抑制细胞以及与细胞免疫治疗整合不完整。本综述综合了这些机制、平台和转化挑战。本综述强调溶瘤病毒（OVs）与 CAR-T、CAR-NK 和TIL（肿瘤浸润淋巴细胞）疗法之间平台特异性的相互作用。OVs 可能增强 CAR-T 的迁移、抗原可用性、局部免疫激活以及对抑制性肿瘤微环境信号的抵抗。在 CAR-NK 疗法中，OV 介导的细胞因子支持和 TME 重塑可能改善募集和活性，尽管抗病毒 NK 反应可能限制病毒持续存在。TIL 疗法被单独考虑，因为它依赖于内源性肿瘤抗原识别而非工程化 CAR 靶向。总体而言，直接的 OV-CAR 证据仍 largely 处于临床前阶段且具有平台特异性，而 OV 与 TILs 及其他免疫疗法联合的早期临床经验在人体研究中更为成熟。然而，这些机制主要由临床前和早期转化证据支持，OV-CAR 联合的直接临床验证仍然有限。抗病毒清除、异质性瘤内感染、中和免疫、递送限制以及可能重叠的炎症毒性也可能限制治疗协同作用。最后，我们提出基于生物标志物的试验设计，纳入病毒药理学、TME转化、抗原呈递能力、细胞产品持久性以及注射病灶和非注射病灶的疗效评估。
Oncolytic virotherapy has evolved from a tumor-selective cytolytic strategy into a programmable immunotherapeutic platform that reshapes the tumor microenvironment (TME). Oncolytic viruses (OVs) selectively infect malignant cells, induce immunogenic cell death, release tumor antigens, and activate innate and adaptive immunity, potentially converting cold tumors into inflamed states. However, clinical translation remains limited by antiviral clearance, heterogeneous delivery, stromal barriers, immunosuppressive cells, and incomplete integration with cellular immunotherapy. This review synthesizes these mechanisms, platforms, and translational challenges. This review emphasizes platform-specific interactions between oncolytic viruses (OVs) and CAR-T, CAR-NK, and tumor-infiltrating lymphocyte (TIL) therapies. OVs may enhance CAR-T trafficking, antigen availability, local immune activation, and resistance to suppressive tumor microenvironmental signals. In CAR-NK therapy, OV-mediated cytokine support and TME remodeling may improve recruitment and activity, although antiviral NK responses can limit viral persistence. TIL therapy is considered separately because it relies on endogenous tumor-antigen recognition rather than engineered CAR targeting. Overall, direct OV-CAR evidence remains largely preclinical and platform-specific, while early clinical experience is more established for OV combinations with TILs and other immunotherapies in human studies. However, these mechanisms are supported predominantly by preclinical and early translational evidence, and direct clinical validation of OV-CAR combinations remains limited. Antiviral clearance, heterogeneous intratumoral infection, neutralizing immunity, delivery constraints, and potentially overlapping inflammatory toxicities may also restrict therapeutic synergy. Finally, we propose biomarker-driven trial designs that incorporate viral pharmacology, TME conversion, antigen-presentation competence, cellular-product persistence, and response assessment in injected and non-injected lesions.
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