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

ABSTRACT

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.