线粒体代谢阻滞纳米辅助反向免疫抗性微环境，以使基于紫杉醇的白蛋白结合的化学免疫疗法敏感
Mitochondrial metabolism blockade nanoadjuvant reversed immune-resistance microenvironment to sensitize albumin-bound paclitaxel-based chemo-immunotherapy
影响因子:14.60000
分区:医学1区 Top / 药学1区
发表日期:2024 Sep
作者:
Zaigang Zhou, Wenjuan Luo, Chunjuan Zheng, Haoxiang Wang, Rui Hu, Hui Deng, Jianliang Shen
摘要
目前，由于肿瘤中的PTX@Alb积累受损而部分由致密胶原蛋白分布介导的PTX@ALB积累受损，因此与白蛋白结合的紫杉醇（PTX@ALB）的功效仍然受到限制。同时，由于PTX@ALB处理后，获得的免疫耐药总是由于加强的程序性细胞死亡凸（PD-L1）表达而产生的，这会导致免疫耐受性。为了填补这些空白，我们新透露，他莫昔芬（TAM）是一种临床广泛使用的辅助治疗，用于乳腺癌，线粒体代谢阻碍的能力也可以用作新型有效的PD-L1和TGF-β双重抑制剂，通过诱导5'-Monophophophate-On-Monophophophate-ostostrated proutectivicativick的磷酸化来诱导。之后，为了获得更重要的效果，通过将靶向线粒体靶向三苯基膦（TPP）的TAM结合制备，然后与TAM一起用白蛋白（ALB）进一步自组装，形成TPP-TAM@Alb@alb@alb nanoparpicles。通过这样做，TPP-TAM@Alb纳米颗粒有效地降低了体外胶原蛋白的表达，然后导致PTX@Alb在4T1肿瘤中的积累增强。此外，TPP-TAM@alb还有效地降低了肿瘤中PD-L1和TGF-β的表达，从而通过增强T细胞浸润来更好地使PTX@Alb介导的化学免疫疗法敏感。总而言之，我们新提出了一种新型的线粒体代谢阻滞策略，以抑制PTX@Alb-耐药性肿瘤，从而进一步支持其更好的临床应用。
Abstract
Currently, the efficacy of albumin-bound paclitaxel (PTX@Alb) is still limited due to the impaired PTX@Alb accumulation in tumors partly mediated by the dense collagen distribution. Meanwhile, acquired immune resistance always occurs due to the enhanced programmed cell death-ligand 1 (PD-L1) expression after PTX@Alb treatment, which then leads to immune tolerance. To fill these gaps, we newly revealed that tamoxifen (TAM), a clinically widely used adjuvant therapy for breast cancer with mitochondrial metabolism blockade capacity, could also be used as a novel effective PD-L1 and TGF-β dual-inhibitor via inducing the phosphorylation of adenosine 5'-monophosphate-activated protein kinase (AMPK) protein. Following this, to obtain a more significant effect, TPP-TAM was prepared by conjugating mitochondria-targeted triphenylphosphine (TPP) with TAM, which then further self-assembled with albumin (Alb) to form TPP-TAM@Alb nanoparticles. By doing this, TPP-TAM@Alb nanoparticles effectively decreased the expression of collagen in vitro, which then led to the enhanced accumulation of PTX@Alb in 4T1 tumors. Besides, TPP-TAM@Alb also effectively decreased the expression of PD-L1 and TGF-β in tumors to better sensitize PTX@Alb-mediated chemo-immunotherapy by enhancing T cell infiltration. All in all, we newly put forward a novel mitochondrial metabolism blockade strategy to inhibit PTX@Alb-resistant tumors, further supporting its better clinical application.