Regulatory mechanism of M2d tumor-associated macrophage-derived exosomal apolipoprotein E on platinum resistance in ovarian cancer
- 1Department of Gynecology, Hainan General Hospital, Affiliated Hainan Hospital of Hainan Medical University
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.
Related
- Integrative bioinformatics screening of a M2 macrophage-associated gene signature for osimertinib resistance
- Engineered protein degradation of farnesyl pyrophosphate synthase is an effective regulatory mechanism to increase monoterpene production in Saccharomyces cerevisiae
- Mechanosignaling Promotes Macrophage Apoptosis Resistance in Pulmonary Fibrosis via Metabolic Reprogramming
- Regulatory mechanism of stem cell scaffold porosity and stiffness on the processes of intramembranous ossification and bone regeneration
- Regulatory role and mechanism of sRNA24 targeting pqsH in Pseudomonas aeruginosa infection immunity
BibTeX
@article{wang2026regulatory,
title = {{Regulatory mechanism of M2d tumor-associated macrophage-derived exosomal apolipoprotein E on platinum resistance in ovarian cancer}},
author = {Chunmei Wang and Ranjun Wu and Genhai Zhu},
journal = {Frontiers in Oncology},
year = {2026},
month = oct,
doi = {10.3389/fonc.2026.1946625},
url = {https://www.frontiersin.org/articles/10.3389/fonc.2026.1946625/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Regulatory mechanism of M2d tumor-associated macrophage-derived exosomal apolipoprotein E on platinum resistance in ovarian cancer
AU - Chunmei Wang
AU - Ranjun Wu
AU - Genhai Zhu
PY - 2026
DA - 2026/10/15
JO - Frontiers in Oncology
DO - 10.3389/fonc.2026.1946625
UR - https://www.frontiersin.org/articles/10.3389/fonc.2026.1946625/full
AB - 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.
SN - 2234-943X
ER -