合成生物学在基于微生物载体肿瘤疫苗设计中的应用

Applications of synthetic biology in developing microbial-vectored cancer vaccines

合成生物学有望创造具备独特优势的抗肿瘤微生物疫苗,合成生物学改造的微生物更能适应肿瘤微环境并在其中富集与增殖,削弱或者逆转免疫抑制细胞的功能,并增强肿瘤抗原的呈递,诱发多种先天与适应性抗肿瘤免疫反应,所以合成生物学已成为肿瘤疫苗研究的重要工具。本文总结了合成生物学在细菌和病毒载体肿瘤疫苗开发中的几个关键应用,其中包括减弱微生物载体毒性的方法,例如去除、失活或修改其致病基因等。讨论了增强它们在肿瘤组织中的趋向性和适应性的策略,如改变它们的细胞入侵分子或引入环境控制的基因表达系统等;也讨论了降低全身毒性的方法。为了充分利用微生物复制引起的肿瘤微环境改变的潜力,多种合成生物学手段被用于改造微生物载体,这些方法包括将外源基因引入微生物基因组,使其生产诸如细胞因子、趋化因子或单克隆抗体等分子,这些分子可以增强先天和适应性免疫细胞的招募和激活,促进肿瘤细胞免疫原性死亡,并增强肿瘤相关抗原的呈递。此外,还探讨了将肿瘤抗原引入载体中的方法,例如不同的装载方式、位置和释放机制。开发微生物载体肿瘤疫苗存在重大挑战,包括安全性问题、抗载体免疫与抗肿瘤免疫的复杂关系和肿瘤生物学的复杂性,克服这些困难将成为未来研究的重要方向。

The development of cancer vaccines is confronted with significant challenges.Synthetic biology emerges as a potent tool for addressing these challenges,due to its ability to modify and engineer microbes capable of adapting to and colonizing on tumor tissues to change the immunosuppressive tumor microenvironments,augment antigen presentations,and stimulate both innate and adaptive immune responses against tumors in situ.This review comments on several pivotal applications of synthetic biology in engineering bacterial and viral vectored cancer vaccines.We start with discussion on methods to mitigate the pathogenicity of bacterial or viral vectors,including the removal,deactivation,or modification of their virulent genes.Furthermore,we address strategies for enhancing their tropism and fitness within tumor tissues,such as the alteration of their cellular entry proteins or the implementation of environmentally controlled gene expression systems.Approaches to minimize their systemic toxicity are also described.To fully harness the potential of tumor microenvironment modifications induced by microbial replication,we underscore studies employing synthetic biology methods,which involve the introduction of foreign genes into the microbial genomes,thereby enabling the production of agents like cytokines,chemokines,or monoclonal antibodies to enhance the recruitment and activation of innate and adaptive cells,promote immunogenic cell death,and augment the presentation of tumor-associated antigens.We also delve into the applications of synthetic biology for the introduction of tumor antigens to the vectors,discussing various loading methods,locations,and releasing mechanisms to generate an optimized tumor-specific immune response.At the end,we highlight substantial challenges that arise in the development of microbial vectored cancer vaccines,including safety considerations,intricate interactions between anti-vector and anti-tumor immunity,and the inherent complexity of tumor biology,and propose strategies for addressing these obstacles.In conclusion,this review emphasizes the crucial role of synthetic biology in the engineering of microbes,which is instrumental in advancing the development of cancer vaccines.