病毒致瘤病毒（OVs）已经成为一种临床治疗模式，可能对逃避常规疗法的癌症，包括中枢神经系统恶性肿瘤，具有潜在的疗效。通过合理设计的组合策略，可以增强OVs的疗效，提高肿瘤选择性细胞毒性和调节肿瘤微环境（TME）。癌症的光动力治疗（PDT）不仅能够直接介导肿瘤细胞死亡，还能够通过激活TME对继发治疗产生增敏作用，从而实现两种潜在具有协同作用的广泛靶点治疗的组合。在本研究中，我们构建了G47Δ-KR，一种临床应用的溃疡性单纯疱疹病毒G47Δ-KR，其表达了光敏化蛋白KillerRed（KR）。通过颜色爱智光照（峰值波长：585-595nm）检测了G47Δ-KR感染人类脑胶质母细胞瘤（GBM）和恶性脑膜瘤（MM）模型的光学性能和细胞毒性效果。在体内，我们测试了光动力-致瘤病毒（PD-OV）疗法,该疗法包括G47Δ-KR的肿瘤内注射，然后激光照射肿瘤（波长：585nm）用于GBM和MM移植物。PD-OV疗法在这些模型中是可行的，并且显示出比单独使用G47Δ-KR（不使用激光）或仅使用激光更强效的抗肿瘤效果。对治疗后的肿瘤样本进行的RNA测序分析表明PD-OV疗法可诱导TME浸润具有不同免疫细胞类型。因此，该研究证明了G47Δ-KR为神经肿瘤恶性肿瘤启用PD-OV疗法的原理，并有待进一步研究以推动潜在的临床转化。版权所有 © 2023。Elsevier B.V.发表。

Oncolytic viruses (OVs) have emerged as a clinical therapeutic modality potentially effective for cancers that evade conventional therapies, including central nervous system malignancies. Rationally designed combinatorial strategies can augment the efficacy of OVs by boosting tumor-selective cytotoxicity and modulating the tumor microenvironment (TME). Photodynamic therapy (PDT) of cancer not only mediates direct neoplastic cell death but also primes the TME to sensitize the tumor to secondary therapies, allowing for the combination of two potentially synergistic therapies with broader targets. Here, we created G47Δ-KR, clinical oncolytic herpes simplex virus G47Δ that expresses photosensitizer protein KillerRed (KR). Optical properties and cytotoxic effects of G47Δ-KR infection followed by amber LED illumination (peak wavelength: 585-595 nm) were examined in human glioblastoma (GBM) and malignant meningioma (MM) models in vitro. G47Δ-KR infection of tumor cells mediated KR expression that was activated by LED and produced reactive oxygen species, leading to cell death that was more robust than G47Δ-KR without light. In vivo, we tested photodynamic-oncolytic virus (PD-OV) therapy employing intratumoral injection of G47Δ-KR followed by laser light tumor irradiation (wavelength: 585 nm) in GBM and MM xenografts. PD-OV therapy was feasible in these models and resulted in potent anti-tumor effects that were superior to G47Δ-KR alone (without laser light) or laser light alone. RNA sequencing analysis of post-treatment tumor samples revealed PD-OV therapy-induced increases in TME infiltration of variable immune cell types. This study thus demonstrated the proof-of-concept that G47Δ-KR enables PD-OV therapy for neuro-oncological malignancies and warrants further research to advance potential clinical translation.Copyright © 2023. Published by Elsevier B.V.