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

Sep 22, 2026

Immune evasion driven by aberrant PD-L1 expression limits cancer immunotherapy outcomes. Mitofusin-2 (MFN2), known for tumor suppression, has an unclear role in regulating immune escape. Using public datasets, clinical specimens, mechanistic assays, single-cell transcriptomic reanalysis, immunocompetent mouse models, and patient-derived organoids, MFN2 was found reduced across cancers and inversely linked to PD-L1 and immunosuppressive signatures. MFN2 restricts EGFR-dependent STAT3 activation and PD-L1 transcription, enhancing CD8+ T-cell cytotoxicity and antitumor immunity. Restoring MFN2 or inhibiting STAT3 decreases PD-L1 and reverses immune suppression.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages16

Reading Time40 min

AccessFree to download

Introduction

Mitochondrial dynamics and MFN2

PD-1/PD-L1 signaling and immune escape

Therapeutic PD-1/PD-L1 blockade and resistance

Results and mechanistic rationale

[www.nature.com/cddis](www.nature.com/cddis) ARTICLE OPEN Mitofusin-2 suppresses tumor immune escape through EGFR/ STAT3-mediated PD-L1 transcription Yan Liu 1,4, Ningning Wang 1,4, Zhenhua Li1,2,4, Na Li 1, Fu Hui1, Xinlei Wang3, Gaoyan Tang 1, Qingyun Zhang 1, Guohua Yu 1, Shuzhen Liu 1 ✉ and Yanhong Ding 1 ✉ © The Author(s) 2026 | | Immune evasion driven by aberrant PD-L1 expression poses a signiﬁcant challenge to the efﬁcacy of cancer immunotherapy. Although Mitofusin-2 (MFN2) is recognized for its role in tumor suppression, its speciﬁc contribution to the regulation of immune escape remains poorly understood. Here, we integrated analyses of public datasets, clinical specimens, and mechanistic experiments in multiple cancer cell lines, immunocompetent mouse models, and patient-derived organoids. A combination of molecular assays and single-cell transcriptomic reanalysis was employed to elucidate how MFN2 inﬂuences tumor immune escape. MFN2 expression was markedly reduced in various cancers and inversely correlated with PD-L1 levels and immunosuppressive gene signatures. Functional assays demonstrated that MFN2 suppresses PD-L1 transcription by limiting EGFR-dependent activation and nuclear translocation of STAT3 . Loss of MFN2 enhanced PD-L1 expression, impaired CD8+ T-cell cytotoxicity, and accelerated tumor growth in immunocompetent mice. Conversely, restoration of MFN2 or pharmacological inhibition of STAT3 decreased PDL1 expression and reactivated antitumor immunity. Our ﬁndings identify MFN2 as a critical suppressor of tumor immune evasion through the EGFR/STAT3–PD-L1 signaling pathway. Targeting this axis may offer a novel strategy to enhance the efﬁcacy of PD-1/ | | | --- | --- | --- | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | PD-L1–based immunotherapy. | | | | | Cell Death and Disease (2026)17:364; [https://doi.org/10.1038/s41419-026-08668-3](https://doi.org/10.1038/s41419-026-08668-3) | | | | | | INTRODUCTION Tumor cells employ multifaceted mechanisms to circumvent immune surveillance, a dynamic process collectively termed cancer immunoediting [1]. This process frequently involves the modulation of immune checkpoint molecules, most notably programmed cell death ligand-1 (PD-L1) [2, 3] . The interaction between programmed cell death-1 (PD-1), typically expressed on activated T cells, and PDL1 on the surface of tumor cells suppresses T-cell activation and impairs cytotoxicity, thereby facilitating immune escape [4, 5] . Aberrant or sustained PD-L1 expression is a hallmark of multiple malignancies—including lung cancer, melanoma, glioma, and breast cancer—where it fosters the establishment of an immunosuppressive tumor microenvironment (TME) [6] . While therapeutic antibodies targeting the PD-1/PD-L1 axis, such as nivolumab and atezolizumab, have revolutionized the clinical management of non-small cell lung cancer, renal cell carcinoma, and various other solid tumors [7–9], the frequent emergence of acquired resistance remains a formidable challenge [10, 11] . Such resistance is often characterized by compensatory PD-L1 upregulation in tumor cells, which further blunts antitumor immunity. Therefore, elucidating the precise molecular mechanisms governing PD-L1 expression is imperative for overcoming immune evasion and optimizing the clinical efﬁcacy of current immunotherapies. Mitochondria are highly dynamic organelles that undergo continuous ﬁssion and fusion to maintain cellular homeostasis and metabolic adaptation [12] . Mitofusin-2 (MFN2), a GTPase anchored to the outer mitochondrial membrane (OMM), serves asa pivotal mediator of mitochondrial fusion [13] . Dysfunctional MFN2 has been implicated in a broad spectrum of pathological conditions, including metabolic disorders, neuropathies, and various malignancies [14–17] . Beyond its canonical roles in mitochondrial dynamics, recent evidence suggests that MFN2 interacts

FAQs

How does Mitofusin-2 influence tumor immune escape?

MFN2 suppresses tumor immune evasion by limiting EGFR/STAT3-mediated PD-L1 transcription. Loss of MFN2 increases PD-L1 and weakens CD8+ T-cell cytotoxicity, promoting tumor growth.

What signaling pathway is implicated in MFN2-mediated regulation of PD-L1?

The study identifies the EGFR/STAT3–PD-L1 signaling axis. MFN2 limits EGFR-dependent activation and nuclear translocation of STAT3, thereby reducing PD-L1 transcription.

What therapeutic implication is suggested by targeting MFN2-related signaling?

Restoring MFN2 or pharmacologically inhibiting STAT3 reduces PD-L1 expression and reactivates antitumor immunity. Targeting this axis is proposed as a strategy to enhance PD-1/PD-L1-based immunotherapy efficacy.

Sep 22, 2026

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