Molecular Weight–Dependent Pyroptosis Induction by Yeast Mannans Through Dectin-2/Syk/NLRP3 Axis Enhances Cisplatin Efficacy in Melanoma Therapy

Abstract

Mannans from various sources have shown to possess antitumor activities. However, the antitumor properties of yeast mannans (YMs) are not yet fully explored, and the mechanisms underlying the antitumor effects of mannans remain unclear. In this study, we prepared three YMs with average molecular weights (Mws) of 21.3 kDa, 41.5 kDa, and 123.2 kDa, designated as YM-L, YM-M, and YM-H, respectively. Cell viability and LDH assays demonstrated that all three YMs exhibited cytotoxic effects on A357 cells in a dose-dependent manner. Morphological observations, flow cytometry analysis, and western blotting revealed that YMs induced membrane rupture and activation of Caspase 1 and GSDMD, which are hallmark characteristics of pyroptosis. Real-time PCR, western blotting, reactive oxygen species (ROS) assays, immunofluorescence assays, and RNA interference assays indicated that YMs induced cell pyroptosis by binding to C-type lectin pathogen receptors Dectin-2, leading to Syk phosphorylation, ROS production, and NLRP3 inflammasome activation. The Mw of YMs was found to significantly affect pyroptosis in A357 cells, with the high Mw YM (YM-H) displaying the highest activity. Moreover, YM-H significantly potentiated cisplatin cytotoxicity both in vitro and in vivo, while demonstrating no observable systemic toxicity, highlighting its promise as an effective adjuvant for combination chemotherapy regimens in melanoma treatment.