Tumor cell-derived microparticles packaging monocarboxylate transporter4 inhibitor fluvastatin suppress lung adenocarcinoma via tumor microenvironment remodeling and improve chemotherapy

• Published in: Chemical engineering journal (Lausanne, Switzerland : 1996) Vol. 451; p. 138972
• Main Authors: Chen, Wenjuan, Tan, Qi, Guo, Mengfei, Liao, Tingting, Li, Yumei, Yin, Zhengrong, Zhou, E., Deng, Jingjing, Li, Minglei, Yang, Zimo, Chen, Jiangbin, Chen, Jiaping, Jia, Zhe, Li, Jingxia, Jin, Yang
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.01.2023
• Subjects: Fluvastatin; Lung adenocarcinoma; Monocarboxylate transporter4; Tumor cell-derived microparticles; Tumor microenvironment; Fluvastatin; Lung adenocarcinoma; Tumor microenvironment; Tumor cell-derived microparticles; Monocarboxylate transporter4
• ISSN: 1385-8947; 1873-3212
• DOI: 10.1016/j.cej.2022.138972

•Fluvastatin suppresses LUAD through disrupting lactate efflux via inhibiting MCT4.•TMPs packaging Fluvastatin (TMP-F) enhance efficacy of Fluvastatin in LUAD.•A combined therapy of TMP-F and Cisplatin further inhibits LUAD progression.•TMP-F and its combination with Cisplatin remodel tumor microenvironment. Monocarboxylate transporter4 (MCT4) is responsible for the efflux of lactate and high expression of MCT4 is related to poor prognosis in multiple cancers. Herein, Fluvastatin, regarded as a lipid-metabolic regulator, has been screened out as an inhibitor of MCT4 for lung adenocarcinoma (LUAD) treatment. As tumor cell-derived microparticles (TMPs) have advantages in low toxicity, biocompatibility and biological targeting, TMPs serve as a highly efficient drug-delivery system to transport Fluvastatin in a relatively low dosage. TMPs encapsulating Fluvastatin (TMP-F), consistent with antitumor function of Fluvastatin, can impede lactate efflux by inhibiting MCT4 expression, resulting in attenuated LUAD progression. TMP-F provokes reversion of immunosuppressive tumor microenvironment (TME) by appealing to infiltration of NK and CD8+ T cells, polarizing M2-type to M1-type macrophages, and decreasing Treg and myeloid-derived suppressor cells (MDSC). In addition, co-administration of TMP-F and chemotherapy Cisplatin still reinforces the antitumor immune response. Meanwhile, TMP-F improves antitumor efficiency of Cisplatin and curbs lung metastasis. Overall, TMP-F or therapeutic alliance with Cisplatin represents a promising strategy for enhancing therapeutic effect on LUAD.