TAMs-derived exosomal PD-L1 drives mitochondrial dysfunction and aberrant fatty acid oxidation via PGC-1α/PPARα axis to promote peritoneal metastasis in epithelial ovarian cancer
- 1Department of Obstetrics and Gynecology, Renji Hospital, Shanghai Jiaotong University School of Medicine, No. 160 Pujian Road, Pudong New Area, Shanghai, 200127 China
- 2Department of Obstetrics and Gynecology, Ningbo Hangzhou Bay Hospital, Ningbo, Zhejiang 315336 China
Abstract
Background: Tumor-associated macrophages (TAMs) are the most abundant immune cells in the ovarian cancer peritoneal microenvironment; however, how their exosomes metabolically reprogram CD8⁺ T cells to induce dysfunction and promote peritoneal metastasis remains unclear.
Methods: M2-type TAMs were induced from RAW264.7 cells using IL-4/IL-13, and exosomes (TAMs-Exo) were isolated using a commercial exosome isolation kit. TAMs-Exo were co-cultured with mouse splenic CD8⁺ T cells to assess T-cell cytotoxicity, proliferative capacity, and secretion of effector molecules; the activation status of the PGC-1α/PPARα/CPT1A axis and mitochondrial function were systematically evaluated using Western blot, JC-1, ATP assays, ROS/lipid peroxidation assays, and FAO rate measurements. Causal validation was performed by stimulating cells with recombinant PD-L1 protein and using shRNA to knockdown PD-L1 in exosomes. An ID8 intraperitoneal metastasis mouse model was established to observe tumor burden and the metabolic remodeling characteristics of peritoneal CD8⁺ T cells.
Results: TAMs-Exo highly express PD-L1 and are effectively taken up by CD8⁺ T cells, significantly inhibiting T-cell cytotoxicity, proliferation, and the secretion of effector molecules (IFN-γ, granzyme B). Mechanistically, TAMs-Exo activates the PGC-1α/PPARα/CPT1A axis via PD-L1, compensatorily increasing the rate of fatty acid oxidation (FAO), but simultaneously leading to a decrease in mitochondrial membrane potential, ATP depletion, and the accumulation of ROS and lipid peroxides—characteristic of mitochondrial dysfunction. Recombinant PD-L1 protein can mimic these effects, whereas knockdown of PD-L1 in exosomes or treatment with the FAO inhibitor (Etomoxir) significantly reverses T-cell dysfunction. In vivo experiments further confirmed that TAMs-Exo promotes ascites formation and an increase in peritoneal metastatic nodules, accompanied by abnormal activation of the PGC-1α/PPARα axis and mitochondrial dysfunction in intraperitoneal CD8⁺ T cells.
Conclusion: TAM-derived exosomes, through the PD-L1 they carry, pathologically overactivate the PGC-1α/PPARα axis in CD8⁺ T cells, inducing mitochondrial dysfunction and abnormal metabolic reprogramming of fatty acid oxidation, thereby driving CD8⁺ T-cell dysfunction and promoting peritoneal metastasis of ovarian cancer. Targeting this metabolic checkpoint—by blocking exosomal PD-L1 or inhibiting excessive FAO flux—may offer a new combination intervention strategy to overcome resistance to immunotherapy in ovarian cancer.
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s13048-026-02277-6.
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BibTeX
@article{ma2026tamsderived,
title = {{TAMs-derived exosomal PD-L1 drives mitochondrial dysfunction and aberrant fatty acid oxidation via PGC-1α/PPARα axis to promote peritoneal metastasis in epithelial ovarian cancer}},
author = {Jun Ma and Qingzhu Wang and Qianqian Cen and Junyan Zhu and Jieru Zhou},
journal = {Journal of Ovarian Research},
year = {2026},
month = sep,
doi = {10.1186/s13048-026-02277-6},
url = {https://doi.org/10.1186/s13048-026-02277-6},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - TAMs-derived exosomal PD-L1 drives mitochondrial dysfunction and aberrant fatty acid oxidation via PGC-1α/PPARα axis to promote peritoneal metastasis in epithelial ovarian cancer
AU - Jun Ma
AU - Qingzhu Wang
AU - Qianqian Cen
AU - Junyan Zhu
AU - Jieru Zhou
PY - 2026
DA - 2026/09/29
JO - Journal of Ovarian Research
DO - 10.1186/s13048-026-02277-6
UR - https://doi.org/10.1186/s13048-026-02277-6
AB - Background: Tumor-associated macrophages (TAMs) are the most abundant immune cells in the ovarian cancer peritoneal microenvironment; however, how their exosomes metabolically reprogram CD8⁺ T cells to induce dysfunction and promote peritoneal metastasis remains unclear. Methods: M2-type TAMs were induced from RAW264.7 cells using IL-4/IL-13, and exosomes (TAMs-Exo) were isolated using a commercial exosome isolation kit. TAMs-Exo were co-cultured with mouse splenic CD8⁺ T cells to assess T-cell cytotoxicity, proliferative capacity, and secretion of effector molecules; the activation status of the PGC-1α/PPARα/CPT1A axis and mitochondrial function were systematically evaluated using Western blot, JC-1, ATP assays, ROS/lipid peroxidation assays, and FAO rate measurements. Causal validation was performed by stimulating cells with recombinant PD-L1 protein and using shRNA to knockdown PD-L1 in exosomes. An ID8 intraperitoneal metastasis mouse model was established to observe tumor burden and the metabolic remodeling characteristics of peritoneal CD8⁺ T cells. Results: TAMs-Exo highly express PD-L1 and are effectively taken up by CD8⁺ T cells, significantly inhibiting T-cell cytotoxicity, proliferation, and the secretion of effector molecules (IFN-γ, granzyme B). Mechanistically, TAMs-Exo activates the PGC-1α/PPARα/CPT1A axis via PD-L1, compensatorily increasing the rate of fatty acid oxidation (FAO), but simultaneously leading to a decrease in mitochondrial membrane potential, ATP depletion, and the accumulation of ROS and lipid peroxides—characteristic of mitochondrial dysfunction. Recombinant PD-L1 protein can mimic these effects, whereas knockdown of PD-L1 in exosomes or treatment with the FAO inhibitor (Etomoxir) significantly reverses T-cell dysfunction. In vivo experiments further confirmed that TAMs-Exo promotes ascites formation and an increase in peritoneal metastatic nodules, accompanied by abnormal activation of the PGC-1α/PPARα axis and mitochondrial dysfunction in intraperitoneal CD8⁺ T cells. Conclusion: TAM-derived exosomes, through the PD-L1 they carry, pathologically overactivate the PGC-1α/PPARα axis in CD8⁺ T cells, inducing mitochondrial dysfunction and abnormal metabolic reprogramming of fatty acid oxidation, thereby driving CD8⁺ T-cell dysfunction and promoting peritoneal metastasis of ovarian cancer. Targeting this metabolic checkpoint—by blocking exosomal PD-L1 or inhibiting excessive FAO flux—may offer a new combination intervention strategy to overcome resistance to immunotherapy in ovarian cancer. Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s13048-026-02277-6.
SN - 1757-2215
ER -