过去几十年从实验室到临床对溶瘤腺病毒进行了广泛的研究。有多种策略增强溶瘤腺病毒的肿瘤靶向性，包括将腺病毒基因组中参与细胞周期节点调控的功能基因（如E1A或E1B）进行突变或（和）利用肿瘤特异性启动子调控E1A基因的靶向转录调控，利用不同血清型腺病毒或RGD基序改变溶瘤腺病毒进入肿瘤细胞方式的靶向转导调控，以及利用细胞载体将溶瘤腺病毒传送至远处的肿瘤部位。溶瘤腺病毒作为一种载体，输送免疫调节基因或治疗性基因，通过增强抗肿瘤免疫，或引起肿瘤细胞凋亡、自杀等产生协同抗肿瘤效应。溶瘤腺病毒临床试验涉及到多种实体瘤，显示其临床应用是安全的，毒性作用轻至中度，患者能很好耐受，但有明确客观抗肿瘤反应的临床病例较少见，联合诸如化、放疗等治疗方法有助于提高临床效果。未来的方向应强化溶瘤腺病毒免疫学相关机制的研究、突破妨碍溶瘤腺病毒研究的一些技术性瓶颈、优化细胞载体、提高溶瘤腺病毒远处传递的靶向性，以及寻找更具潜能的肿瘤干细胞作为靶点。此外，需要扩大临床试验的研究范围和加强与其他治疗方式特别是免疫治疗联合应用的研究。

Extensive investigations of oncolytic adenoviruse (OA) from the laboratory to the clinic have been made in the past decades. There are a few strategies for improving the potential targeted therapy of OA in cancer, including transcriptional targeting by mutating functional genes (such as E1A or E1B ) of Ad genome which is involved in the control of cell cycle checkpoints in cells and/or utilizing tumor-specific promoter control of E1A expression, transductional targeting by changing tropism of OA with different types or incorporated by RGD motif into tumor cells, and cell carriers for delivery of OA to the distant tumor sites. Enhanced anti-tumor immune response, apoptosis or suicide of tumor cells elicited by OA, as vector, enabling express immunoregulatory or therapeutic genes contribute to generate synergetic antitumor effects with OA. Clinical trials of OA for various solid tumors have been carried out, in which the application for patients is safe, presenting well tolerated, mild to moderate adverse events, though few objective tumor responses to patients have been observed. Combination of OA with other therapies, such as chemotherapy or radiotherapy can improve clinical efficacy. Future directions of OA development should be focus on strengthening the research on OA-associated immunological mechanisms, breaking through some technical bottlenecks hampering deep studies of OA, optimizing cell carries for targeting of OA to distant tumor sites, and looking for more potential targets such cancer stem cells. In addition, enlarging the range of clinical OA trials and reinforcing the investigations to combine OA with other therapeutic approaches, particularly with immunotherapy, are needed.

国家自然科学基金资助项目（No. 30972804, No.81172162）