Int J Biol Macromol 2025 Jul 07;320Pt 2:145830. doi: 10.1016/j.ijbiomac.2025.145830.

Fucosylated chondroitin sulfate exerts in vitro anti-tumor property through manipulating the metabolism related polarization of macrophages.

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Tumor associated macrophages (TAMs) participate in the development of tumor, which was reported to dominantly be alternatively activated M2 subtype. Metabolic reprogramming of TAMs into tumor-inhibiting M1 type has shown to be a promising treatment strategy. In this study, we firstly demonstrated fucosylated chondroitin sulfate isolated from sea cucumber Stichopus chloronotus (fCS-Sc) exerted anti-tumor effects. fCS-Sc intervened the metabolism-polarization crosstalk of macrophages and reprogrammed M2 RAW264.7 cells to M1 subtype. fCS-Sc converted IL-4 and IL-13 mediated M2-like RAW264.7 cells to M1 subtype and enhanced the M1-like anti-tumor immunity via suppressing STAT6 signaling and promoting TLRs-NF-κB pathway. The reprogramming effect of fCS-Sc on M2 subtype macrophages were closely related to its metabolism. fCS-Sc markedly elevated the glycolytic pathway and down-regulated fatty acid oxidation pathway. Furthermore, the co-culture assay of M2 subtype RAW264.7 cells and 4 T1 cells demonstrated that fCS-Sc reprogrammed the M2 macrophages to M1 subtype and facilitated its tumor-killing ability. This study will contribute to the application of fCS-Sc as an ancillary drug in anti-tumor treatments.

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