Immune checkpoint crosstalk between LAG-3 and CD39/CD73 in glioblastoma: dual-pathway regulation of metabolic exhaustion and therapeutic reversal strategies

Glioblastoma (GBM) represents an immunologically "cold" and metabolically suppressive tumor characterized by profound T-cell exhaustion, hypoxia-induced adenosinergic signaling, and resistance to checkpoint blockade. Converging evidence identifies lymphocyte-activation gene 3 (LAG-3) and the CD39/CD73 ectonucleotidase cascade as cooperative regulators of immune dysfunction within the GBM microenvironment. LAG-3 attenuates TCR/CD3 signaling and disrupts mitochondrial oxidative phosphorylation, diminishing effector T-cell persistence. Concurrently, CD39/CD73-mediated ATP hydrolysis elevates adenosine levels, activating A₂A receptors that inhibit glycolysis, suppress IFN-γ, and promote Treg and M2 macrophage polarization. Spatial and single-cell omics reveal co-localization of LAG-3⁺ exhausted T cells with CD73⁺ stromal and myeloid niches, suggesting a reciprocal immunometabolic feedback loop reinforcing exhaustion. This review elucidates the molecular crosstalk between LAG-3 signaling and the adenosine pathway, emphasizing key metabolic regulators including AMPK, mTOR, and HIF-1α. It further evaluates therapeutic strategies combining LAG-3 or PD-1 blockade with adenosine receptor antagonists or CD73 inhibitors to restore T-cell bioenergetics and antitumor activity. By integrating mechanistic immunometabolism with translational insights, this review establishes a dual-pathway framework of checkpoint synergy underlying resistance in GBM and proposes rational combination immunotherapies to reverse metabolic and immune exhaustion.