超越“冷转热”：溶瘤病毒疗法作为免疫肿瘤学的下一个基石
Beyond cold to hot: oncolytic virotherapy as the next cornerstone of immuno-oncology
这篇观点文章指出，免疫检查点抑制剂和早期溶瘤病毒都依赖患者体内已有的肿瘤特异性T细胞，因而存在疗效上限。作者认为下一代溶瘤病毒可在瘤内感染引发免疫原性细胞死亡，释放肿瘤全蛋白组，在佐剂样环境下原位启动针对患者个体新抗原的T细胞，相当于“抗原不可知的原位癌症疫苗”。文章提出四大发展支柱：瘤内疫苗作为免疫点火、优化载荷激活抗原呈递细胞、修订疗效评价标准以捕捉延迟和远端应答、以及将溶瘤病毒作为免疫肿瘤学基础平台。文中提到早期临床数据已显示T细胞克隆谱拓宽、远端肿瘤消退及对免疫检查点抑制剂无效患者的生存获益。
为什么推荐给您：观点综述提出溶瘤病毒新定位并整合早期临床线索，属值得关注的概念推进
不需要生物学背景，多打比方
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摘要Abstract
Oncolytic virotherapy has evolved from a platform predicated on lysis of cancer cells into a sophisticated system for intratumoural immune reprogramming; the prevailing 'cold-to-hot' paradigm captures only part of this potential. A fundamental limitation shared by immune checkpoint inhibitors (ICIs) and early-generation oncolytic viruses (OVs) is a reliance on pre-existing tumour-specific T cells (TSTs), which presents an immunological ceiling that constrains antitumour activity - given that these agents have a limited capacity to generate TSTs de novo. Next-generation OVs overcome this constraint by functioning as agents for antigen-agnostic in situ cancer vaccination: intratumoural infection triggers immunogenic cell death, releasing potentially the full cancer proteome under pathogen-associated and/or damage-associated molecular pattern adjuvant conditions, thereby driving T cell priming against patient-specific neoantigens. In this Perspective, we delineate four pillars for the development of next-generation OVs. First, intratumoural vaccination as immunological ignition, with initial clinical data demonstrating T cell clonotype broadening, abscopal tumour regression and survival benefit in patients with ICI-refractory disease. Second, optimized payload-driven immune priming to hyperactivate antigen-presenting cells. Third, revised efficacy evaluation and end points using response criteria as well as novel biological correlates that better capture delayed and abscopal immune-mediated tumour control. Fourth, OV as the foundational immuno-oncology platform: according to the 'triple-A' framework encompassing admission, availability and activation of TSTs, next-generation, payload-engineered OVs uniquely satisfy all prerequisites for antitumour immunity simultaneously, with evidence from clinical trials of such agents supporting an 'OV-prime, ICI-amplify' strategy. Notably, OVs are systemic immune-reprogramming platforms that are delivered locally, not local therapies with incidental systemic effects.