Tumor-intrinsic FDFT1 determines coordinated macrophage anti-tumor immunity

Area of Science:

• Oncology
• Immunology
• Metabolic Regulation

Background:

• Macrophage anti-tumor efficacy relies on inflammatory activation and phagocytosis.
• The role of tumor-intrinsic metabolic regulators in controlling both macrophage functions is not fully understood.

Purpose of the Study:

• To identify tumor-intrinsic metabolic regulators that simultaneously control macrophage activation and phagocytosis.
• To elucidate the mechanisms by which such regulators promote tumor progression.
• To evaluate FDFT1 as a potential therapeutic target for cancer treatment.

Main Methods:

• Screening for tumor-intrinsic metabolic regulators affecting macrophage functions.
• Investigating the molecular mechanisms of FDFT1 action, including protein-protein interactions and pathway analysis.
• Utilizing mouse tumor models and clinical data for validation.
• Testing a small-molecule FDFT1 inhibitor (FDFT1-I) in preclinical models.

Main Results:

• Farnesyl-diphosphate farnesyltransferase 1 (FDFT1) was identified as a key regulator inhibiting both macrophage activation and phagocytosis.
• FDFT1 promotes STAT3 phosphorylation, leading to PD-L1 expression and suppressed phagocytosis.
• FDFT1 stabilizes cholesterol 25-hydroxylase (CH25H), increasing 25-hydroxycholesterol (25HC) and suppressing macrophage inflammatory activation.
• FDFT1 inhibition by FDFT1-I restored anti-tumor immunity in preclinical models.

Conclusions:

• Tumor-intrinsic FDFT1 promotes tumor development by simultaneously inhibiting macrophage inflammatory activation and phagocytic function.
• FDFT1 represents a novel therapeutic target for enhancing anti-tumor immunity and treating cancer.