HHLA2 promotes immune evasion in EGFR-mutant lung cancer by inhibiting CD8 T cell glutamine metabolism via KIR3DL3 interaction.

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality, and EGFR-mutant tumors show limited response to current immunotherapy. The immunosuppressive tumor microenvironment, particularly metabolic constraints on effector T cells, is increasingly recognized as a major barrier to effective anti-tumor responses. HHLA2, a B7 family member frequently elevated in EGFR-mutant NSCLC, has an incompletely defined role in immune escape. In this study, we demonstrate that tumor-derived HHLA2 engages the inhibitory receptor KIR3DL3 on CD8 T cells, driving T cell exhaustion through metabolic reprogramming of amino acid utilization. HHLA2-KIR3DL3 signaling suppresses glutamine utilization through ERK/MAPK-dependent repression of SLC1A5, SLC38A2, and ADHFE1, key glutamine transporters and metabolic enzymes, thereby inducing metabolic insufficiency and dysfunctional cytokine production in CD8 T cells, including reduced IFN-γ, TNF-α, and increased IL-10. Disruption of this axis-via HHLA2 deletion or antibody blockade-restored T cell metabolism and effector function, leading to attenuated tumor progression in humanized mouse models. Notably, HHLA2/KIR3DL3 inhibition synergized with EGFR tyrosine kinase inhibitors to enhance anti-tumor immunity and suppress tumor progression. Together, these findings identify HHLA2-KIR3DL3 as a key immunosuppressive pathway in EGFR-mutant NSCLC and may provide a rationale for therapeutic targeting to improve clinical outcomes.