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

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.