Mefloquine enhances the efficacy of anti-PD-1 immunotherapy via IFN-γ-STAT1-IRF1-LPCAT3-induced ferroptosis in tumors

Area of Science:

• Immunology
• Oncology
• Biochemistry

Background:

• Ferroptosis is crucial for anti-programmed cell death 1 (PD-1) immunotherapy efficacy.
• Molecular mechanisms linking tumor ferroptosis to anti-PD-1 immunotherapy in melanoma and lung cancer remain unclear.

Purpose of the Study:

• To elucidate the molecular mechanisms by which tumor ferroptosis sensitizes melanoma and lung cancer to anti-PD-1 immunotherapy.
• To investigate the role of mefloquine (Mef) in inducing ferroptosis and enhancing anti-PD-1 therapy.

Main Methods:

• In vitro and in vivo experiments evaluated Mef's effects on ferroptosis and cancer cell survival.
• RNA sequencing, qRT-PCR, western blotting, and ChIP-qPCR identified Mef's regulatory pathway for LPCAT3.
• Clinical data and single-cell RNA sequencing analyzed LPCAT3's correlation with anti-PD-1 immunotherapy efficacy.

Main Results:

• Mefloquine (Mef) induces ferroptosis and sensitizes melanoma and lung cancer to anti-PD-1 immunotherapy, especially when combined with interferon-gamma (IFN-γ).
• Mef upregulates lysophosphatidylcholine acyltransferase 3 (LPCAT3) expression via the IFN-γ-induced STAT1-IRF1 signaling pathway, crucial for Mef+IFN-γ-mediated ferroptosis.
• Reduced LPCAT3 expression in melanoma patients correlates with lower immunotherapy efficacy, while higher expression is linked to better outcomes.

Conclusions:

• Mefloquine (Mef) represents a novel therapeutic strategy to enhance anti-PD-1 immunotherapy by targeting the LPCAT3 regulatory pathway.
• The study reveals a new mechanism for LPCAT3 regulation and its critical role in sensitizing tumors to immunotherapy.