MEK inhibition overcomes chemoimmunotherapy resistance by inducing CXCL10 in cancer cells

Cancer Cell. 2022 Feb 14;40(2):136-152.e12. doi: 10.1016/j.ccell.2021.12.009. Epub 2022 Jan 19.


Chemotherapy with anti PD-1/PD-L1 antibodies has become the standard of care for patients with metastatic non-small cell lung cancer (mNSCLC). Using lung tumor models, where pemetrexed and cisplatin (PEM/CDDP) chemotherapy remains unable to synergize with immune checkpoint inhibitors (ICIs), we linked the failure of this treatment with its inability to induce CXCL10 expression and CD8+ T cell recruitment. Using drug screening, we showed that combining a MEK inhibitor (MEKi) with PEM/CDDP triggers CXCL10 secretion by cancer cells and CD8+ T cell recruitment, sensitizing it to ICIs. PEM/CDDP plus a MEKi promotes optineurin (OPTN)-dependent mitophagy, resulting in CXCL10 production in a mitochondrial DNA- and TLR9-dependent manner. TLR9 or autophagy/mitophagy inhibition abolishes the anti-tumor efficacy of PEM/CDDP plus MEKi/anti-PD-L1 therapy. In human NSCLCs, high OPTN, TLR9, and CXCL10 expression is associated with a better response to ICIs. Our results underline the role of TLR9- and OPTN-dependent mitophagy in enhancing chemoimmunotherapy efficacy.

Keywords: CXCL10; MEK inhibitor; TLR9; chemotherapy; immunogenic cell death; immunotherapy; lung cancer; mitophagy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Autophagy / drug effects
  • Autophagy / genetics
  • B7-H1 Antigen / antagonists & inhibitors
  • Biomarkers, Tumor
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / pathology
  • Cell Line, Tumor
  • Chemokine CXCL10 / genetics*
  • Chemokine CXCL10 / metabolism
  • Disease Models, Animal
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics*
  • Drug Synergism
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Immune Checkpoint Proteins / genetics
  • Immune Checkpoint Proteins / metabolism
  • Mice
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors*
  • Mitophagy / genetics
  • Mitophagy / immunology
  • Neoplasms / drug therapy
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Protein Binding
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use
  • Signal Transduction
  • Tumor Microenvironment / genetics
  • Tumor Microenvironment / immunology
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • B7-H1 Antigen
  • Biomarkers, Tumor
  • CD274 protein, human
  • CXCL10 protein, human
  • Chemokine CXCL10
  • Immune Checkpoint Proteins
  • Protein Kinase Inhibitors
  • Mitogen-Activated Protein Kinase Kinases