Imiquimod Exerts Antitumor Effects by Inducing Immunogenic Cell Death and Is Enhanced by the Glycolytic Inhibitor 2-Deoxyglucose

J Invest Dermatol. 2020 Sep;140(9):1771-1783.e6. doi: 10.1016/j.jid.2019.12.039. Epub 2020 Feb 6.


The induction of immunogenic cell death (ICD) in cancer cells triggers specific immune responses against the same cancer cells. Imiquimod (IMQ) is a synthetic ligand of toll-like receptor 7 that exerts antitumor activity by stimulating cell-mediated immunity or by directly inducing apoptosis. Whether IMQ causes tumors to undergo ICD and elicits a specific antitumor immune response is unknown. We demonstrated that IMQ-induced ICD-associated features, including the surface exposure of calreticulin and the secretion of adenosine triphosphate and HMGB1, were mediated by ROS and endoplasmic reticulum stress. In a B16F10 melanoma mouse model, vaccinating mice with IMQ-induced ICD cell lysate or directly injecting IMQ in situ reduced tumor growth that was mediated by inducing tumor-specific T-cell proliferation, promoting tumor-specific cytotoxic killing by CD8+ T cells, and increasing the infiltration of various immune cells into tumor lesions. The ICD-associated features were crucial in the induction of specific antitumor immunity in vivo. The glycolytic inhibitor 2-deoxyglucose enhanced IMQ-induced ICD-associated features and strengthened the antitumor immunity mediated by IMQ-induced ICD cell lysate in p53-mutant cancer cells, which were IMQ-resistant in vitro. We conclude that IMQ is an authentic ICD inducer and provide a concept connecting IMQ-induced cancer cell death and antitumor immune responses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Cell Line, Tumor / transplantation
  • Deoxyglucose / pharmacology*
  • Deoxyglucose / therapeutic use
  • Drug Synergism
  • Glycolysis / drug effects
  • Humans
  • Imiquimod / pharmacology*
  • Imiquimod / therapeutic use
  • Immunogenic Cell Death / drug effects*
  • Male
  • Melanoma, Experimental / drug therapy*
  • Melanoma, Experimental / immunology
  • Melanoma, Experimental / pathology
  • Mice
  • Skin Neoplasms / drug therapy*
  • Skin Neoplasms / immunology
  • Skin Neoplasms / pathology


  • Deoxyglucose
  • Imiquimod