Citalopram exhibits immune-dependent anti-tumor effects by modulating C5aR1⁺ TAMs

Area of Science:

• Immunology
• Pharmacology
• Oncology

Background:

• Selective serotonin reuptake inhibitors (SSRIs) are linked to reduced cancer risk and possess anti-tumor properties.
• The precise molecular targets and mechanisms underlying SSRI anti-cancer effects are not fully understood.
• Hepatocellular carcinoma (HCC) remains a significant global health challenge, necessitating novel therapeutic strategies.

Purpose of the Study:

• To investigate the immune-dependent anti-tumor effects of citalopram in hepatocellular carcinoma (HCC).
• To identify the molecular target of citalopram's anti-HCC activity, distinct from its known serotonin transporter inhibition.
• To explore the potential of repurposing SSRIs, like citalopram, for cancer therapy.

Main Methods:

• Drug repurposing approaches including global reverse gene expression profiling.
• Drug affinity responsive target stability (DARTS) assay and molecular docking.
• In vivo studies assessing citalopram's impact on macrophage phagocytosis and CD8+ T cell immunity in HCC models.

Main Results:

• Citalopram demonstrated immune-dependent anti-tumor effects in HCC, independent of the serotonin transporter.
• Complement component 5a receptor 1 (C5aR1) was identified as a novel molecular target of citalopram.
• Citalopram treatment enhanced macrophage phagocytosis and promoted CD8+ T cell-mediated anti-tumor immunity, with C5aR1 and CD8+ T cells being crucial for efficacy.

Conclusions:

• Citalopram exerts anti-HCC effects by targeting C5aR1, thereby modulating the tumor microenvironment and enhancing anti-tumor immunity.
• The study highlights the immunomodulatory role of citalopram in inducing anti-tumor responses.
• These findings support the potential repurposing of SSRIs as a promising therapeutic avenue for HCC treatment.