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Combined MEK1/2 and Autophagy Inhibition Suppresses Tumor Growth via STING-Mediated Type I Interferon Response in

Chengqiang Sun1, Zheng Gao1, Enfu Dong1

  • 1Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Institute and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Zhongshan Hospital, Fudan University, Shanghai, China.

Cancer Science
|June 2, 2026
PubMed

Insights

MEK inhibitors trigger protective autophagy in intrahepatic cholangiocarcinoma (iCCA) cells, limiting anti-tumor immunity. Blocking autophagy alongside MEK inhibitors enhances immune response and suppresses tumor growth, offering a novel therapeutic strategy for iCCA.

Area of Science:

  • Oncology
  • Cell Biology
  • Immunology

Background:

  • The RAF-MEK-ERK pathway is implicated in intrahepatic cholangiocarcinoma (iCCA) pathogenesis.
  • MEK inhibitors (MEKis) show limited efficacy as monotherapy in iCCA due to unclear adaptive resistance mechanisms.

Purpose of the Study:

  • To elucidate the adaptive mechanisms underlying MEKi resistance in iCCA.
  • To investigate the role of autophagy in MEKi efficacy.
  • To explore combination therapies targeting the MEK-autophagy-STING axis.

Main Methods:

  • Investigated MEK inhibition effects on autophagy, ROS, and mitophagy in iCCA cells.
  • Utilized pharmacological and genetic inhibition of autophagy.
  • Assessed cGAS-STING-TBK1 pathway activation and type I interferon signaling.
  • Evaluated combined MEK and autophagy inhibition in iCCA xenograft models.

Main Results:

  • MEK inhibition induced protective autophagy via LKB1-ULK1 activation and suppressed ERK-RSK signaling.
  • MEK inhibition led to ROS accumulation and PINK1/Parkin-mediated mitophagy, limiting cGAS-STING-TBK1 activation.
  • Autophagy inhibition enhanced STING-mediated type I interferon signaling and sensitized iCCA cells to MEKi.
  • Combined MEK and autophagy inhibition suppressed tumor growth in vivo.

Conclusions:

  • MEK inhibition triggers an adaptive autophagic response that dampens innate immune sensing in iCCA.
  • Targeting the MEK-autophagy-STING axis represents a promising strategy to enhance MEKi efficacy in iCCA.
  • This study reveals a critical link between MAPK signaling, autophagy, and innate immunity in cancer therapy.
Keywords:
MEKautophagycGAS‐STING signaling pathwayinterferon type Iintrahepatic cholangiocarcinoma

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