Mitofusin-2 suppresses tumor immune escape through EGFR/STAT3-mediated PD-L1 transcription

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Aberrant Programmed Death-Ligand 1 (PD-L1) expression drives immune evasion in cancer, limiting immunotherapy effectiveness.
• Mitofusin-2 (MFN2) is a known tumor suppressor, but its role in regulating tumor immune escape is unclear.

Purpose of the Study:

• To investigate the function of MFN2 in regulating tumor immune escape and its association with PD-L1 expression.
• To elucidate the molecular mechanisms by which MFN2 influences the EGFR/STAT3 signaling pathway and PD-L1 transcription.

Main Methods:

• Integrated analysis of public datasets, clinical specimens, and mechanistic experiments in cancer cell lines, mouse models, and patient-derived organoids.
• Employed molecular assays and single-cell transcriptomic reanalysis to determine MFN2's impact on immune escape.
• Utilized functional assays to assess the effects of MFN2 loss or restoration on PD-L1 expression and anti-tumor immunity.

Main Results:

• MFN2 expression was significantly reduced in various cancers, inversely correlating with PD-L1 levels and immunosuppressive gene signatures.
• MFN2 suppressed PD-L1 transcription by limiting EGFR-dependent STAT3 activation and nuclear translocation.
• Loss of MFN2 increased PD-L1, impaired CD8+ T-cell function, and accelerated tumor growth; MFN2 restoration or STAT3 inhibition reversed these effects.

Conclusions:

• MFN2 acts as a critical suppressor of tumor immune evasion by regulating the EGFR/STAT3-PD-L1 axis.
• Targeting the MFN2-EGFR/STAT3-PD-L1 pathway presents a potential strategy to enhance PD-1/PD-L1-based cancer immunotherapy.