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.