Abstract

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.