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Inhibiting Arginine Metabolism via ALDH2/ARG2 Axis Blockade Potentiates Immune Checkpoint Inhibitors in Colorectal

Lu Cai1, Yonglong Cao1, Jiawei Zhang1

  • 1Southern Medical University Hospital of Integrated Traditional Chinese and Western Medicine, Southern Medical University, Guangzhou, China.

Molecular Cancer Therapeutics
|September 26, 2025
PubMed

Insights

Aldehyde dehydrogenase 2 (ALDH2) depletes L-arginine in colorectal cancer, hindering CD8+ T-cell function and immunotherapy response. Targeting arginase 2 (ARG2) with immune checkpoint blockade shows promise for resistant tumors.

Area of Science:

  • Oncology
  • Immunology
  • Metabolism

Background:

  • Metabolic reprogramming is crucial in colorectal cancer (CRC) immunotherapy resistance.
  • The role of L-arginine metabolism in CRC immunity is not well understood.

Purpose of the Study:

  • To investigate the role of L-arginine metabolism in CRC immunotherapy resistance.
  • To identify novel therapeutic targets for overcoming resistance.

Main Methods:

  • Metabolomic profiling to identify key metabolic regulators.
  • High-performance liquid chromatography (HPLC) to measure L-arginine levels.
  • Mechanistic studies involving gene expression and cell proliferation assays.
  • Analysis of tumor response to immune checkpoint blockade (ICB).

Main Results:

  • Aldehyde dehydrogenase 2 (ALDH2) was identified as a key regulator depleting intracellular and extracellular L-arginine in CRC cells.
  • ALDH2 overexpression suppressed CD8+ T-cell proliferation and antitumor efficacy by reducing L-arginine availability.
  • ALDH2 upregulates PBX3, enhancing ARG2 transcription and L-arginine catabolism, which impairs CD8+ T-cell glycolysis and function.
  • ALDH2-high tumors showed resistance to ICB, while combined ARG2 inhibition and ICB restored antitumor immunity.

Conclusions:

  • ALDH2-driven L-arginine depletion is a mechanism of immunotherapy resistance in CRC.
  • Arginase 2 (ARG2) is a potential therapeutic target for enhancing ICB efficacy.
  • Combined metabolic and immunologic intervention strategies may overcome ICB resistance in CRC.

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