Dual Neuromodulation Remodels Neuro–Immune Crosstalk and Chemokine Network for Combating Postoperative Progression of Prostate Cancer

The autonomic nerves drive prostate cancer (PCa) progression, yet a strategy for dual modulation of sympathetic and parasympathetic nerves remains undeveloped. Here, building on the multicenter clinical findings, we develop a personalized nanotechnology-enabled dual neurotherapy (denoted as ADNT) for PCa. The ADNT employs hybrid nanovesicles composed of autologous tumor cell membranes and functionalized liposomes to codeliver the β-blocker and the muscarinic receptor antagonist to autonomic nerves in residual tumor. In refractory, highly invasive, and orthotopic murine PCa models, the ADNT effectively delays postoperative recurrence and metastasis. Light-sheet fluorescence microscopy visually confirms the downregulation of autonomic nerve infiltration. Cytometry by time-of-flight reveals that ADNT remodels neuro-immune crosstalk and the chemokine network, promoting antitumor immune response and suppressing tumor progression. Additionally, ADNT also alleviates cancer-associated cachexia and anxiety. Combined with immune checkpoint blockade, ADNT induces complete responses in 100% of mice. Immunofluorescence staining of human PCa specimens confirms the clinical translatability of ADNT, establishing ADNT as a promising therapeutic strategy for PCa.