Regulatory mechanism of M2d tumor-associated macrophage-derived exosomal apolipoprotein E on platinum resistance in ovarian cancer.

Authors

Chunmei Wang, Ranjun Wu, Genhai Zhu

Published in

Frontiers in oncology. Volume 16. Pages 1946625. Epub Oct 15, 2026.

Abstract

Platinum-based chemotherapy plus cytoreductive surgery represents the standard first-line therapy for ovarian cancer (OC), which yields robust early therapeutic responses in most patients. However, platinum resistance is a formidable clinical hurdle, and how macrophages mediate drug resistance within the OC tumor microenvironment remains poorly understood.
We cultured SKOV3 OC cells and THP-1 monocytes, induced THP-1 differentiation into M2d tumor-associated macrophages. Stable apolipoprotein E (ApoE) -overexpressing SKOV3 cell lines were constructed via lentiviral transfection and puromycin screening. We established nude mouse subcutaneous xenograft models with mixed tumor cells and M2d macrophages, administered cisplatin treatment and collected tumor tissues after sacrifice by cervical dislocation. RNA was extracted from tumor samples to conduct RT-qPCR for gene expression detection. Tumor tissue sections were prepared for HE staining, TUNEL apoptosis staining, and Western blot analysis to detect ApoE and phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway protein expression.
Using nude mouse subcutaneous xenograft models, we demonstrated that M2d-type tumor-associated macrophages (M2d TAMs) promote platinum resistance and elevate tumoral ApoE levels. In OC xenografts with stable ApoE overexpression, cisplatin-induced apoptosis was profoundly repressed, resulting in reduced cisplatin sensitivity, while this inhibitory effect was not observed in the empty vector control group. Mechanistically, ApoE activates the PI3K/AKT/mTOR signaling cascade to counteract cisplatin cytotoxicity by suppressing cell death and sustaining pro-survival signals.
Overall, this study reveals that M2d TAMs induce platinum resistance in OC cells via exosomes carrying ApoE.

PMID:
42959057
Bibliographic data and abstract were imported from PubMed on 30 Oct 2026.

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