Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, Sichuan Med-X Center for Materials, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, Sichuan Med-X Center for Materials, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
Acta Biomater. 2022 Aug;148:181-193. doi: 10.1016/j.actbio.2022.05.045. Epub 2022 May 29.
Cancer-associated fibroblasts (CAFs)-mediated metabolic support plays a vital role in tumorigenesis. The metabolic network between cancer cells and CAFs may serve as promising targets for cancer therapy. Here, aiming at targeted blockade of the metabolic support of CAFs to cancer cells, a biomimetic nanocarrier is designed by coating solid lipid nanoparticles containing chemotherapeutic paclitaxel (PTX) and glycolysis inhibitor PFK15 with hybrid membranes of cancer cells and activated fibroblasts. The nanoparticles possess outstanding dual-targeting ability which can simultaneously target cancer cells and CAFs. The encapsulated glycolysis inhibitor PFK15 can prevent the glycolysis of cancer cells and CAFs at the same time, thus increasing the chemosensitivity of cancer cells and blocking the metabolic support of CAFs to cancer cells. The results showed that the combination of PTX and PFK15 exhibited synergistic effects and inhibited tumor growth effectively. Moreover, the biomimetic nanoparticles obviously reduced the lactate production in the tumor microenvironment, leading to activated immune responses and enhanced tumor suppression. This work presents a facile strategy to destroy the metabolic network between cancer cells and CAFs, and proves the potential to elevate chemo-immunotherapy by glycolysis inhibition. STATEMENT OF SIGNIFICANCE: In many solid tumors, most cancer cells produce energy and carry out biosynthesis through glycolysis, even in aerobic conditions. As the main tumor stromal cells, cancer-associated fibroblasts (CAFs) usually turn oxidative phosphorylation into aerobic glycolysis with metabolic reprogramming and provide high-energy glycolytic metabolites for cancer cells. The metabolic network between cancer cells and CAFs is regarded as the vulnerability among cancer cells. Moreover, lactate produced by cancer cells and CAFs through glycolysis often leads to the immunosuppressive tumor microenvironment. The present study provides an effective approach to destroy the metabolic network between cancer cells and CAFs and greatly improves the antitumor immune response by reducing lactate production, which serves as a promising strategy for combined chemo-immunotherapy mediated by glycolysis.
癌症相关成纤维细胞 (CAFs) 介导的代谢支持在肿瘤发生中起着至关重要的作用。癌细胞和 CAFs 之间的代谢网络可能成为癌症治疗的有前途的靶点。在这里，为了靶向阻断 CAFs 对癌细胞的代谢支持，设计了一种仿生纳米载体，该载体通过将含有化疗药物紫杉醇 (PTX) 和糖酵解抑制剂 PFK15 的固体脂质纳米颗粒用癌细胞和激活的成纤维细胞的混合膜进行包被。该纳米颗粒具有出色的双重靶向能力，能够同时靶向癌细胞和 CAFs。包封的糖酵解抑制剂 PFK15 可以同时阻止癌细胞和 CAFs 的糖酵解，从而提高癌细胞的化疗敏感性并阻断 CAFs 对癌细胞的代谢支持。结果表明，PTX 和 PFK15 的组合表现出协同作用，有效抑制肿瘤生长。此外，仿生纳米颗粒明显减少了肿瘤微环境中的乳酸产生，导致激活的免疫反应和增强的肿瘤抑制。这项工作提出了一种简单的策略来破坏癌细胞和 CAFs 之间的代谢网络，并证明通过抑制糖酵解来提高化疗-免疫治疗的潜力。
在许多实体瘤中，大多数癌细胞即使在有氧条件下也通过糖酵解产生能量并进行生物合成。作为主要的肿瘤基质细胞，癌症相关成纤维细胞 (CAFs) 通常通过代谢重编程将氧化磷酸化转化为有氧糖酵解，并为癌细胞提供高能糖酵解代谢物。癌细胞和 CAFs 之间的代谢网络被认为是癌细胞之间的脆弱性。此外，癌细胞和 CAFs 通过糖酵解产生的乳酸常常导致免疫抑制的肿瘤微环境。本研究提供了一种有效破坏癌细胞和 CAFs 之间代谢网络的方法，并通过减少乳酸产生极大地提高了抗肿瘤免疫反应，这为通过糖酵解介导的联合化疗-免疫治疗提供了一种很有前途的策略。
