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

The RAF-MEK-ERK pathway contributes to many human cancers, including intrahepatic cholangiocarcinoma (iCCA). Although MEK is an important therapeutic target, MEK inhibitors (MEKis) have limited efficacy as monotherapy in iCCA, and the underlying adaptive mechanisms remain unclear. Here, we show that MEK inhibition induces protective autophagy in iCCA cells. Mechanistically, MEK inhibition suppressed ERK-RSK signaling, activated the LKB1-ULK1 pathway, and promoted autophagy. MEK inhibition also increased reactive oxygen species (ROS) accumulation and activated PINK1/Parkin-mediated mitophagy. This autophagic response limited activation of the cGAS-STING-TBK1 pathway. Pharmacological or genetic inhibition of autophagy during MEK inhibition enhanced STING-mediated type I interferon signaling, increased IFN-α and IFN-β expression, and sensitized iCCA cells to MEKi treatment. Consistently, combined MEK and autophagy inhibition suppressed tumor growth in xenograft-bearing nude mice. These findings identify a link between MAPK signaling, autophagy, and innate immune sensing and support targeting the MEK-autophagy-STING axis to improve MEKi efficacy in iCCA.