Orlistat facilitates immunotherapy via AKT-FOXO3a-FOXM1-mediated PD-L1 suppression

Area of Science:

• Immunology
• Oncology
• Pharmacology

Background:

• Immunotherapy targeting CTLA-4 and PD-L1 has advanced cancer treatment.
• Further improvements in cancer immunotherapy efficacy are still needed.

Purpose of the Study:

• To investigate orlistat's potential to enhance CTLA-4 blockade immunotherapy.
• To elucidate the mechanisms by which orlistat boosts antitumor immunity.

Main Methods:

• In vivo and in vitro experiments were conducted.
• Orlistat's effects on PD-L1 expression, ISGs, MHC-I, AKT, FOXO3a, and p-STAT1 were analyzed.

Main Results:

• Orlistat suppressed tumor cell PD-L1 expression and boosted ISGs and MHC-I.
• Orlistat inhibited AKT activity, leading to FOXO3a accumulation and suppressed PD-L1 transcription via FOXM1.
• Orlistat enhanced p-STAT1, upregulating ISGs and MHC-I.

Conclusions:

• Orlistat enhances anti-CTLA-4 immunotherapy efficacy.
• Orlistat modulates the immune response to promote antitumor immunotherapy when combined with CTLA-4 blockade.