Cell Metabolism

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

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.

Tyrosine catabolism enhances genotoxic chemotherapy by suppressing translesion DNA synthesis in epithelial ovarian cancer

Amino acid metabolism has been actively investigated as a potential target for antitumor therapy, but how it may alter the response to genotoxic chemotherapy remains largely unknown. Here, we report that the depletion of fumarylacetoacetate hydrolase (FAH), an enzyme that catalyzes the final step of tyrosine catabolism, reduced chemosensitivity in epithelial ovarian cancer (EOC). The expression level of FAH correlated significantly with chemotherapy efficacy in patients with EOC. Mechanistically, under genotoxic chemotherapy, FAH is oxidized at Met308 and translocates to the nucleus, where FAH-mediated tyrosine catabolism predominantly supplies fumarate. FAH-produced fumarate binds directly to REV1, resulting in the suppression of translesion DNA synthesis (TLS) and improved chemosensitivity. Furthermore, in vivo tyrosine supplementation improves sensitivity to genotoxic chemotherapeutics and reduces the occurrence of therapy resistance. Our findings reveal a unique role for tyrosine-derived fumarate in the regulation of TLS and may be exploited to improve genotoxic chemotherapy through dietary tyrosine supplementation.