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Updated: Aug 18, 2025

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Metformin Inducing the Change of Functional and Exhausted Phenotypic Tumor-Infiltrated Lymphocytes and the

Ruibin Wang1, Yuchen Li2, Yanjie Zhao3

  • 1Department of Emergency, Beijing Shijitan Hospital, Capital Medical University, Beijing, People's Republic of China.

Breast Cancer (Dove Medical Press)
|December 9, 2022
PubMed
Abstract

Insights

Metformin enhances anti-tumor immunity in triple-negative breast cancer (TNBC) by boosting functional tumor-infiltrated lymphocytes (TILs) via the JNK pathway. It also reduces exhausted TILs, suggesting potential for immunotherapy combinations.

Area of Science:

  • Oncology
  • Immunology
  • Pharmacology

Background:

  • Triple-negative breast cancer (TNBC) is an aggressive cancer subtype.
  • Metformin shows potential in inhibiting cancer cell proliferation.
  • Understanding metformin's effect on tumor-infiltrated lymphocytes (TILs) in TNBC is crucial.

Purpose of the Study:

  • To investigate metformin's regulatory effect on phenotypic TILs in TNBC.
  • To elucidate the underlying mechanisms of metformin's action in the TNBC microenvironment.

Main Methods:

  • Microarray analysis of 4T1 cells treated with metformin.
  • In vivo studies using BALB/c mice with 4T1 cells and JNK modulation.
  • Immunofluorescence staining to visualize phenotypic TILs.

Main Results:

  • Metformin inhibited 4T1 cell proliferation and increased JNK expression in vitro.
  • In vivo, metformin significantly increased CD4+ and CD8+ TILs, associated with the JNK pathway.
  • Metformin reduced exhausted TILs (CD4+/PD-1+, CD8+/PD-1+) and suppressed IL-6 and TNF-α levels.

Conclusions:

  • Metformin enhances functional TILs via the JNK pathway and reduces exhausted TILs independently in TNBC.
  • Metformin demonstrates potential for combination therapy with immunotherapy in TNBC.
  • Further research is needed to fully explore metformin's mechanisms in TNBC.
Keywords:
C-Jun N-terminal kinasemetforminphenotypic tumor-infiltrated lymphocytestriple-negative breast cancer

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