实体瘤的治疗总是受到固有的肿瘤物理微环境(TPME)的阻碍,这些微环境具有紧凑而刚性的细胞外基质(ECM)微观结构。在这里,我们介绍纳豆激酶(NKase),一种溶栓保健药物,全面调节TPME,以全面增强各种治疗方式。瘤内注射NKase不仅降解主要ECM成分纤连蛋白,而且抑制癌症相关成纤维细胞(CAFs)产生纤维化,导致肿瘤僵硬度下降,增强灌注,和缺氧缓解。NKase介导的TPME调节显着促进治疗剂的肿瘤积累,导致有效的化疗而不引起副作用。此外,基于放射增敏剂的肿瘤放疗的增强也通过瘤内注射NKase的预处理实现,这可能归因于NKase治疗的肿瘤中氧饱和度升高。此外,一个异种移植的人乳腺MDB-MA-231肿瘤模型,以评估NKase对嵌合抗原受体(CAR)-T细胞治疗的影响,说明NKase的预处理可以促进CAR-T细胞浸润到肿瘤中,因此对肿瘤抑制有益。这些发现证明了NKase调节的TPME作为通过各种治疗普遍增强实体瘤治疗功效的转化策略的巨大前景。
The therapy of solid tumors is always hampered by the intrinsic tumor physical microenvironment (TPME) featured with compact and rigid extracellular matrix (ECM) microstructures. Herein, we introduce nattokinase (NKase), a thrombolytic healthcare drug, to comprehensively regulate the TPME for versatile enhancement of various therapy modalities. Intratumoral injection of NKase not only degrades the major ECM component fibronectin but also inhibits cancer-associated fibroblasts (CAFs) in generating fibrosis, resulting in decreased tumor stiffness, enhanced perfusion, and hypoxia alleviation. The NKase-mediated regulation of the TPME significantly promotes the tumoral accumulation of therapeutic agents, leading to efficient chemotherapy without inducing side effects. Additionally, the enhancement of tumor radiotherapy based on radiosensitizers was also achieved by the pretreatment of intratumorally injected NKase, which could be ascribed to the elevated oxygen saturation level in NKase-treated tumors. Moreover, a xenografted human breast MDB-MA-231 tumor model is established to evaluate the influence of NKase on chimeric antigen receptor (CAR)-T cell therapy, illustrating that the pretreatment of NKase could boost the infiltration of CAR-T cells into tumors and thus be a benefit for tumor inhibition. These findings demonstrate the great promise of the NKase-regulated TPME as a translational strategy for universal enhancement of therapeutic efficacy in solid tumors by various treatments.