Overcoming acquired resistance to PD-1 inhibitor with the addition of metformin in small cell lung cancer (SCLC)

Yeseul Kim, Elena Vagia, Pedro Viveiros, Cyra Y. Kang, Ju Young Lee, Gahyun Gim, Sukjoo Cho, Horyun Choi, Leeseul Kim, Inae Park, Jaeyoun Choi, Young Kwang Chae*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

15 Scopus citations


Metformin has been widely used as the treatment of type II diabetes mellitus for its anti-hyperglycemic effect. In recent years, it has also been extensively studied for its anti-cancer effect as it diminishes immune exhaustion of CD8 + tumor-infiltrating lymphocytes (TILs). It decreases apoptosis of CD8 + TILs, thereby enhancing T cell-mediated immune response to tumor cells. Here, we present a unique case of a patient with small cell lung cancer (SCLC) who exhibited an overall partial response as per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1) since starting metformin in combination with nivolumab therapy. Our patient had been treated with nivolumab monotherapy for 2 years until she had progression of disease. After she was started on metformin along with nivolumab therapy, she has shown a significant durable response for over 6 months. Many patients develop resistance to immunotherapy such as antibodies against cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed cell death 1 (PD-1), and programmed cell death ligand 1 (PD-L1). Tumor hypoxia is one of the resistance factors. Signals activated by hypoxic environments in tumors are associated with decreased sensitivity to the PD-1 blockade. Metformin inhibits oxygen consumption in tumor cells in vitro and in vivo, reducing intratumoral hypoxia. These data suggest that metformin can improve susceptibility to anti-PD-1 treatment. To the best of our knowledge, our case is the first reported example demonstrating a proof-of-concept that metformin can contribute to overcoming acquired resistance to PD-1 inhibitors.

Original languageEnglish (US)
Pages (from-to)961-965
Number of pages5
JournalCancer Immunology, Immunotherapy
Issue number4
StatePublished - Apr 2021


  • Acquired resistance
  • Durable response
  • Immunotherapy
  • Metformin
  • Small cell lung cancer

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology
  • Cancer Research


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