Metformin promotes anticancer activity of NK cells in a p38 MAPK dependent manner

Wenjiao Xia1, Xin Qi1, Mingfeng Li1

  • 1Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, P. R. China.

Oncoimmunology
|November 8, 2021
PubMed

Insights

Metformin enhances natural killer (NK) cell activity, boosting the immune system's ability to fight cancer. This finding supports metformin's potential as a novel cancer therapy by improving NK cell-mediated tumor cell killing.

Area of Science:

  • Immunology
  • Pharmacology
  • Oncology

Background:

  • Metformin, a type 2 diabetes drug, shows potential antitumor effects through immune activation.
  • The specific impact of metformin on natural killer (NK) cells remains unclear.

Purpose of the Study:

  • To investigate metformin's role in activating NK cells for cancer treatment.
  • To elucidate the mechanisms behind metformin-induced NK cell enhancement.

Main Methods:

  • Assessed NK-92 cell line and primary NK cells' cytolytic activity upon metformin exposure.
  • Analyzed intracellular signaling pathways (JAK/STAT, AKT/mTOR, p38 MAPK, AMPK) using western blotting.
  • Evaluated metformin's efficacy in vivo using mouse models for lymphoma and melanoma.
  • Examined the combination therapy of metformin with anti-PD-1 antibodies in melanoma models.

Main Results:

  • Metformin significantly enhanced NK cell-mediated cytotoxicity in vitro.
  • Metformin activated JAK/STAT and AKT/mTOR pathways in a p38 MAPK-dependent manner.
  • In vivo studies demonstrated improved NK cell cancer surveillance and tumor infiltration.
  • Combination therapy with anti-PD-1 antibodies improved melanoma treatment response.

Conclusions:

  • Metformin potentiates NK cell effector functions, offering a new avenue for cancer immunotherapy.
  • Metformin's mechanism involves specific signaling pathway activation, distinct from AMPK.
  • Findings support metformin's development as an adjunct cancer therapy to enhance immune responses.

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