2. Academic Validation
  3. Serotonin-licensed macrophages potentiate chemoresistance via inositol metabolic crosstalk in ovarian cancer

Serotonin-licensed macrophages potentiate chemoresistance via inositol metabolic crosstalk in ovarian cancer

  • Cell Metab. 2025 Dec 17:S1550-4131(25)00495-4. doi: 10.1016/j.cmet.2025.11.011.
Jie Li 1,  Jingyi Lu 2,  Cuimiao Zheng 2,  Xi Huang 2,  Haoyuan Li 3,  Qiuwen Mai 4,  Siqi Chen 5,  Zhou Zhou 5,  Jiayu Zhu 5,  Tiantian Yu 6,  Manman Xu 4,  Hao Tan 4,  Chun-Min Zhang 7,  Qinglei Gao 8,  Junxiu Liu 9,  Chaoyun Pan 10
Affiliations

Affiliations

  • 1 Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China; Department of Obstetrics and Gynecology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China. Electronic address: lijie295@mail.sysu.edu.cn.
  • 2 Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China; Department of Biochemistry and Molecular Biology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
  • 3 Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China; Department of Obstetrics and Gynecology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
  • 4 Department of Obstetrics and Gynecology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
  • 5 Department of Biochemistry and Molecular Biology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
  • 6 Metabolomics Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong 510080, China.
  • 7 Pediatric Intensive Care Unit, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510120, China.
  • 8 National Clinical Research Center for Obstetrics and Gynecology, Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China. Electronic address: qingleigao@hotmail.com.
  • 9 Department of Obstetrics and Gynecology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China. Electronic address: liujxiu@mail.sysu.edu.cn.
  • 10 Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China; Department of Biochemistry and Molecular Biology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China; Metabolomics Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong 510080, China. Electronic address: panchy27@mail.sysu.edu.cn.
PMID: 41412121 DOI: 10.1016/j.cmet.2025.11.011
Abstract

Therapeutic resistance in solid tumors frequently stems from enhanced homologous recombination (HR) repair capacity, yet systemic regulators of this pathway remain poorly defined. Here, we identify a serotonin-sensitive tumor-associated macrophage (TAM) subpopulation that orchestrates inositol metabolic crosstalk to potentiate HR repair in Cancer cells. This TAM subset exhibited marked enrichment in ovarian tumors with low response to chemotherapy. Mechanistically, peripheral serotonin activates these TAMs via serotonin receptor HTR7, triggering extracellular vesicle (EV) secretion enriched with inositol metabolic Enzymes PI4K2A and ITPKC. EV-mediated transfer of these metabolic Enzymes elevates nuclear inositol-1,3,4,5-tetraphosphate (IP4) in Cancer cells, where IP4 directly binds MRE11 and facilitates MRE11-DNA binding and HR repair. Attenuating peripheral serotonin using fluoxetine-a selective serotonin reuptake inhibitor (SSRI) antidepressant-ablates TAM-derived EV delivering of inositol metabolic Enzymes and sensitizes tumors to cisplatin/PARP Inhibitor (PARPi). Our study unveils a systemic serotonin-primed metabolic crosstalk within the tumor microenvironment that potentiates chemoresistance, revealing targetable HR repair regulation beyond cancer-cell-autonomous mechanisms.

Keywords

HR repair; cancer metabolism; chemotherapy; macrophage; ovarian cancer; serotonin.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z