Laboratory of Chemical Biology and State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, 130022, P. R. China.
School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, Anhui, 230026, P. R. China.
Small. 2023 Aug;19(35):e2301519. doi: 10.1002/smll.202301519. Epub 2023 May 8.
Combination therapies involving metabolic regulation and immune checkpoint blockade are considered an encouraging new strategy for cancer therapy. However, the effective utilization of combination therapies for activating tumor-associated macrophages (TAMs) remains challenging. Herein, a lactate-catalyzed chemodynamic approach to activate the therapeutic genome editing of signal-regulatory protein α (SIRPα) to reprogram TAMs and improve cancer immunotherapy is proposed. This system is constructed by encapsulating lactate oxidase (LOx) and clustered regularly interspaced short palindromic repeat-mediated SIRPα genome-editing plasmids in a metal-organic framework (MOF). The genome-editing system is released and activated by acidic pyruvate, which is produced by the LOx-catalyzed oxidation of lactate. The synergy between lactate exhaustion and SIRPα signal blockade can enhance the phagocytic ability of TAMs and promote the repolarization of TAMs to the antitumorigenic M1 phenotype. Lactate exhaustion-induced CD47-SIRPα blockade efficiently improves macrophage antitumor immune responses and effectively reverses the immunosuppressive tumor microenvironment to inhibit tumor growth, as demonstrated by in vitro and in vivo studies. This study provides a facile strategy for engineering TAMs in situ by combining CRISPR-mediated SIRPα knockout with lactate exhaustion for effective immunotherapy.
联合代谢调控和免疫检查点阻断的治疗方法被认为是癌症治疗的一种有前途的新策略。然而，有效地利用联合治疗方法来激活肿瘤相关巨噬细胞（TAMs）仍然具有挑战性。在此，提出了一种通过乳酸催化的化学动力学方法来激活信号调节蛋白α（SIRPα）的治疗性基因编辑，以重新编程 TAMs 并改善癌症免疫治疗。该系统通过将乳酸氧化酶（LOx）和簇状规则间隔的短回文重复介导的 SIRPα 基因编辑质粒包封在金属有机骨架（MOF）中构建。基因编辑系统通过 LOx 催化的乳酸氧化产生的酸性丙酮酸释放和激活。乳酸耗竭和 SIRPα 信号阻断的协同作用可以增强 TAMs 的吞噬能力，并促进 TAMs 向抗肿瘤 M1 表型的重极化。体外和体内研究表明，乳酸耗竭诱导的 CD47-SIRPα 阻断可有效增强巨噬细胞的抗肿瘤免疫反应，并有效逆转免疫抑制性肿瘤微环境以抑制肿瘤生长。这项研究为通过 CRISPR 介导的 SIRPα 敲除与乳酸耗竭相结合来原位工程化 TAMs 提供了一种简便的策略，以实现有效的免疫治疗。
