中山大学潘超云小组宣布他们的研究认为5-羟色胺相关巨噬细胞通过肌醇代谢串扰增强卵巢癌的化疗耐药。该项研究成果发表在2025年12月17日出版的《细胞—代谢》上。

研究人员发现了一个对血清素敏感的肿瘤相关巨噬细胞（TAM）亚群，该亚群协调肌醇代谢串扰，以增强癌细胞中的HR修复。这个TAM亚群在对化疗反应低的卵巢肿瘤中表现出显著的富集。机制上，外周5 -羟色胺通过5 -羟色胺受体HTR7激活这些TAMs，触发细胞外囊泡（EV）分泌富集肌醇代谢酶PI4K2A和ITPKC。EV介导的这些代谢酶的转移升高了癌细胞中的核肌醇-1,3,4,5-四磷酸（IP4），其中IP4直接结合MRE11并促进MRE11-DNA结合和HR修复。氟西汀是一种选择性5 -羟色胺再摄取抑制剂（SSRI）抗抑郁药，可抑制TAM衍生的EV传递肌醇代谢酶，并使肿瘤对顺铂/PARP抑制剂（PARPi）敏感。他们的研究揭示了肿瘤微环境中系统性的5 -羟色胺引发的代谢串音，增强了化疗耐药，揭示了超越癌细胞自主机制的靶向HR修复调节。

据悉，实体肿瘤的治疗耐药通常源于增强的同源物重组（HR）修复能力，但这一途径的系统调节因子仍不明确。

附：英文原文

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

Author: Jie Li, Jingyi Lu, Cuimiao Zheng, Xi Huang, Haoyuan Li, Qiuwen Mai, Siqi Chen, Zhou Zhou, Jiayu Zhu, Tiantian Yu, Manman Xu, Hao Tan, Chun-min Zhang, Qinglei Gao, Junxiu Liu, Chaoyun Pan

Issue&Volume: 2025-12-17

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.

DOI: 10.1016/j.cmet.2025.11.011

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(25)00495-4