Asparagine enhances LCK signalling to potentiate CD8+ T-cell activation and anti-tumour responses

Nutrient availability is central for T-cell functions and immune responses. Here we report that CD8(+) T-cell activation and anti-tumour responses are strongly potentiated by the non-essential amino acid Asn. Increased Asn levels enhance CD8(+) T-cell activation and effector functions against tumour cells in vitro and in vivo. Conversely, restriction of dietary Asn, ASNase administration or inhibition of the Asn transporter SLC1A5 impairs the activity and responses of CD8(+) T cells. Mechanistically, Asn does not directly alter cellular metabolic fluxes; it instead binds the SRC-family protein tyrosine kinase LCK and orchestrates LCK phosphorylation at Tyr 394 and 505, thereby leading to enhanced LCK activity and T-cell-receptor signalling. Thus, our findings reveal a critical and metabolism-independent role for Asn in the direct modulation of the adaptive immune response by controlling T-cell activation and efficacy, and further uncover that LCK is a natural Asn sensor signalling Asn sufficiency to T-cell functions. Wu et al. show that instead of altering cellular metabolism, asparagine directly binds to LCK and enhances T-cell-receptor signalling, thereby promoting CD8(+) T-cell-mediated anti-tumour responses.