目前，白蛋白结合型紫杉醇 (PTX@Alb) 的疗效仍然有限，因为肿瘤中 PTX@Alb 的积累受损，部分原因是密集的胶原蛋白分布介导的。同时，由于PTX@Alb治疗后程序性细胞死亡配体1（PD-L1）表达增强，导致获得性免疫抵抗，从而导致免疫耐受。为了填补这些空白，我们最新发现，临床上广泛使用的具有线粒体代谢阻断能力的乳腺癌辅助治疗药物他莫昔芬（TAM），也可以通过诱导PD-L1和TGF-β双抑制剂作为一种新型有效的PD-L1和TGF-β双重抑制剂。腺苷 5'-单磷酸激活蛋白激酶 (AMPK) 蛋白的磷酸化。随后，为了获得更显着的效果，通过将线粒体靶向的三苯基膦（TPP）与TAM缀合来制备TPP-TAM，然后进一步与白蛋白（Alb）自组装形成TPP-TAM@Alb纳米颗粒。通过这样做，TPP-TAM@Alb 纳米粒子在体外有效降低了胶原蛋白的表达，从而导致 4T1 肿瘤中 PTX@Alb 的积累增加。此外，TPP-TAM@Alb 还有效降低肿瘤中 PD-L1 和 TGF-β 的表达，通过增强 T 细胞浸润来更好地提高 PTX@Alb 介导的化疗免疫治疗的敏感性。总而言之，我们新提出了一种新的线粒体代谢阻断策略来抑制 PTX@Alb 耐药肿瘤，进一步支持其更好的临床应用。© 2024 作者。

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.© 2024 The Authors.