Targeting tumor-associated sympathetic nerves orchestrates tertiary lymphoid structures to enhance PD-1/PD-L1 blockade efficacy.

Tumor-innervating peripheral nerves have been implicated in tumor initiation and progression; however, the contribution of sympathetic nerve infiltration to gastric cancer (GC) prognosis and immunotherapy response remains unclear. Here, we demonstrate that high TH fiber density in GC is associated with poorer survival and reduced responsiveness to immune checkpoint blockade (ICB) response. Sympathetic innervation inversely correlated with CXCL13 CD8 T-cell infiltration and tertiary lymphoid structure (TLS) abundance. In murine models, chemical sympathectomy using 6-OHDA suppressed tumor growth, enhanced CXCL13 CD8 T-cell effector function, promoted TLS formation, and reduced lung metastasis. Mechanistically, sympathetic neural activity restrains CD8 T-cell-mediated anti-tumor immunity via β-adrenergic signaling. Therapeutically, the combination of the β-blocker Atenolol and αPD-L1 therapy synergistically enhanced anti-tumor immunity, highlighting sympathetic signaling as therapeutic targets to potentiate immunotherapy. Pan-cancer analyses further revealed negative associations between TH expression, immune activation signatures, and αPD-1 therapy benefit. Collectively, our findings demonstrate that sympathetic nerve infiltration constrains anti-tumor immunity and limits the efficacy of αPD-L1 therapy in GC. Targeting adrenergic signaling to relieve this immunosuppressive constraint-by promoting CXCL13 CD8 T cells and TLS formation-may improve immunotherapy outcomes in GC and potentially other malignancies.