SMPDM3B-loaded extracellular vesicles from tumor-associated macrophages drive ovarian cancer chemoresistance by inhibiting the cGAS/STING pathway.

Tumor-associated macrophages (TAMs) are implicated in the enhanced chemoresistance of ovarian cancer (OC), with extracellular vesicles (EVs) serving as important mechanism mediating intercellular communication. This study aimed to investigate the role of TAMs-derived EVs in OC chemoresistance. Chemoresistance of OC cell lines were evaluated after treated with cisplatin. EVs were isolated from TAMs, and OC cells were then co-cultured with TAMs or treated with TAMs-derived EVs. Cell viability was measured by CCK-8 and colony formation assays, while cell apoptosis was evaluated by TUNEL and flow cytometry. A xenograft model was employed to examine the interaction between OC cells and TAMs in vivo. Our results showed that co-culture with TAMs or incubation with TAMs-derived EVs increased chemoresistance in OC cells, as evidenced by increased IC50 values and colony formation numbers, as well as decreased apoptosis. Additionally, SMPDL3B protein levels were upregulated by TAMs co-culture or EVs treatment. However, pretreatment with the EVs secretion inhibitor GW4869 reversed the effect of TAMs co-culture on OC cell chemoresistance. Mechanistically, SMPDL3B upregulation in OC cells increased chemoresistance by inhibiting the cGAS/STING pathway, and the pathway activator ADU-S100 reversed its effect. Notably, TAMs co-cultured with OC cells overexpressing SMPDL3B were induced toward an M2-associated macrophage phenotype, which was reversed by ADU-S100 pretreatment. Finally, the xenograft model showed that TAMs co-injection promoted tumor progression, whereas SMPDL3B knockdown in TAMs abolished this effect. Collectively, this study demonstrates that TAMs-derived EVs transfer SMPDL3B to OC cells, where it inhibits the cGAS/STING pathway and thereby enhances chemoresistance.