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ATG5-mediated inducible autophagy sustains CAR-T cell durability under solid tumor stress

Sang-Eun Jung1,2, Minji Lim1,2, Hyungwoo Jeong1,2

  • 1Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea.

Frontiers in Immunology
|May 8, 2026
PubMed

Insights

Enhancing autophagy in chimeric antigen receptor (CAR)-T cells using ATG5 improves their function and persistence in solid tumors. This strategy boosts CAR-T cell antitumor efficacy and survival, offering a promising approach for immunotherapy.

Area of Science:

  • Immunology
  • Cell Biology
  • Cancer Research

Background:

  • Autophagy is a stress adaptation pathway in T cells, but its role in CAR-T cell function in solid tumors is unclear.
  • Understanding autophagy's impact on CAR-T cells is crucial for improving solid tumor immunotherapies.

Purpose of the Study:

  • To investigate if ATG5-mediated autophagy regulation enhances CAR-T cell durability under tumor-associated stress.
  • To determine the effect of ATG5 overexpression on CAR-T cell function and antitumor activity.

Main Methods:

  • Generated ATG5-overexpressing (OE) CAR-T cells.
  • Assessed autophagy flux in response to stimuli under immunosuppressive conditions.
  • Evaluated CAR-T cell cytotoxic activity, cytokine production, and oxidative stress in vitro.
  • Tested in vivo antitumor efficacy in IR-preconditioned solid tumor models.

Main Results:

  • ATG5 OE CAR-T cells showed enhanced inducible autophagy flux, not basal levels.
  • In vitro, ATG5 OE CAR-T cells maintained cytotoxicity and cytokine production, with reduced oxidative stress.
  • In vivo, ATG5 OE CAR-T cells demonstrated improved tumor control and survival, with sustained effector function.

Conclusions:

  • Reinforcing inducible autophagy via ATG5 promotes CAR-T cell maintenance under tumor stress.
  • Targeting ATG5-mediated autophagy is a viable strategy to enhance CAR-T cell persistence in solid tumor immunotherapy.
Keywords:
ATG5 overexpressionCAR-T cell therapyCAR-T persistenceautophagytumor microenvironment

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