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

Abstract Metabolic reprogramming constitutes a key mechanism driving immunotherapy resistance in colorectal cancer although the immunomodulatory role of L-arginine metabolism remains poorly defined. Through metabolomic profiling, we identified aldehyde dehydrogenase 2 (ALDH2) as a critical regulator depleting intracellular L-arginine pools in colorectal cancer cells. High-performance liquid chromatography analysis of cell supernatants further demonstrated that ALDH2 overexpression significantly diminishes extracellular L-arginine availability. Functionally, this arginine deficiency suppressed CD8+ T-cell proliferation while inducing the attenuation of antitumor efficacy. Mechanistic studies revealed that ALDH2 upregulates pre–B-cell leukemia homeobox 3 (PBX3), which enhances arginase 2 (ARG2) transcription to promote L-arginine catabolism. This process suppresses glycolysis in CD8+ T cells, ultimately compromising their effector functions. Notably, ALDH2-high tumors exhibited resistance to immune checkpoint blockade (ICB), whereas combinatorial ARG2 inhibition and ICB therapy synergistically restored antitumor immunity. These findings nominate ARG2 as a novel therapeutic target and propose dual metabolic–immunologic intervention as a promising strategy for ICB-resistant colorectal cancer.