Work

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

Year: 2026

Type: article

Abstract: Background: 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. Methods: 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. Results: 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. Conclusions: Overall, this study reveals that M2d TAMs induce platinum resistance in OC cells via exosomes carrying ApoE.

Source: Frontiers in Oncology

DOI: 10.3389/fonc.2026.1946625

Authors: Chunmei Wang, Ranjun Wu, Genhai Zhu

Institutions: Hainan General Hospital, Hainan Medical University

Language: English

Topic: Extracellular vesicles in disease

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,801