Serotonin drives chemoresistance | Nature Immunology – Immunology Research

Enhanced homologous recombination (HR) repair capacity causes chemoresistance in cancer cells, but how this pathway is regulated remains unclear. In Cell Metabolism Li et al. find that serotonin activates tumor-associated macrophages (TAMs) to secrete extracellular vesicles (EVs), resulting in increased levels of nuclear inositol-1,3,4,5-tetraphosphate (IP4) in cancer cells, which facilitates HR repair. In a mouse model of ovarian cancer, M2-like TAMs were increased in chemoresistant tumors, which were enriched for inositol metabolism and expressed the serotonin receptor HTR7. In individuals with ovarian cancer, HTR7 expression negatively correlated with response to chemotherapy. HTR7⁺ TAMs released more EVs than HTR7⁻ TAMs and serotonin stimulation could enhance EV release. In vitro, EVs from HTR7⁺ TAMs reduced chemotherapy-induced apoptosis in cancer cells and in vivo administration of an HTR7 antagonist to tumor-bearing mice reduced EV secretion from HTR7⁺ TAMs and suppressed chemoresistance. EVs from HTR7⁺ TAMs contained the inositol metabolic enzymes PI4K2A and ITPKC, which were delivered to cancer cells, resulting in increased nuclear IP4 and enhanced HR repair efficiency. Treating tumor-bearing mice with the selective serotonin reuptake inhibitor fluoxetine depleted systemic serotonin, delayed tumor progression and reduced chemoresistant relapses. Together, these data suggest that antidepressants could resensitize some tumors to chemotherapy.

Original reference: Cell Metab. https://doi.org/10.1016/j.cmet.2025.11.011 (2025)