Tumor-derived L-arginine acts as a metabolic checkpoint to sustain CAR T cell anti-tumor memory

ABSTRACT:

Metabolic competition within the tumor microenvironment (TME) severely impairs the efficacy and persistence of chimeric antigen receptor (CAR) T cells in solid tumors. While targeting tumor metabolism is a promising therapeutic avenue, its precise implementation remains a challenge. Here, we discover that pharmacological glutamine blockade unexpectedly reprograms tumor cell metabolism, triggering a compensatory biosynthetic pathway for L-arginine (L-Arg) via upregulation of ASS1 and suppression of ARG2. To exploit this finding therapeutically, we developed a tumor-targeted delivery platform using nanoengineered, DON-conjugated CAR T cells (DNP-CAR T). This approach locally inhibits glutaminolysis, which in turn induces ASS1-driven L-Arg biosynthesis to replenish the TCA cycle via anaplerosis, elevating intratumoral L-Arg by 2.74-fold. The enriched L-Arg pool functions as a metabolic checkpoint messenger, instructing a shift in CAR T cell metabolism toward oxidative phosphorylation (OXPHOS) and promoting a memory-like phenotype, which enhances their infiltration and cytotoxicity. Consequently, DNP-CAR T cells achieve sustained tumor control and significantly prolong survival in vivo. Our work defines L-arginine as a critical immunometabolic node and provides a translatable, combined cell therapy strategy to overcome metabolic immunosuppression in solid tumors.

INSTRUMENT(S): Liquid Chromatography MS -

PROVIDER: MTBLS14035 | MetaboLights | 2026-10-23

REPOSITORIES: MetaboLights