Dual PD-1/IL-2Rα targeting restores CD8+ T cell fitness via STAT5/CD47 axis in SMARCA4-deficient NSCLC.

SMARCA4-deficient non-small cell lung cancer (NSCLC) is a genomically distinct and clinically aggressive subtype characterized by primary resistance to immune checkpoint inhibitors. This study identifies that SMARCA4 deficiency profoundly disrupts the interleukin (IL)-2-STAT5 signaling pathway in tumor-infiltrating CD8+ T cells by suppressing IL-2 receptor alpha (IL-2Rα) (CD25) expression, leading to severe T cell exhaustion and resistance to PD-1 inhibition. An engineered PD-1/IL-2 bispecific antibody (bsAb) with α-receptor-targeting activity reverses this defect across multiple preclinical models by co-engaging PD-1 and delivering a CD25-targeted IL-2 signal, thereby restoring STAT5 activation and effector function in exhausted CD8+ T cells. Mechanistically, PD-1/IL-2 bsAb-driven STAT5 activation transcriptionally upregulates CD47 on CD8+ T cells, which shields them from macrophage-mediated phagocytosis and enhances T cell survival in the tumor microenvironment. These findings delineate a role for the IL-2-STAT5-CD47 axis in immune evasion and suggest reactivating this pathway with PD-1/IL-2 bsAb may represent a therapeutic strategy to overcome resistance in this subtype.