Nanoadaptor–driven targeted dephosphorylation of STAT3 for cancer immunotherapy

Persistently activated signal transducer and activator of transcription 3 (STAT3) drives tumor malignancy and suppresses antitumor immunity, positioning it as an attractive immunotherapeutic target. Although numerous STAT3 inhibitors have been developed, their limited clinical success has motivated alternative strategies to restore the inactive state of STAT3 by blocking its phosphorylation. Here, we develop a Targeted Dephosphorylation NanoAdaptor (TDNA) that induces proximity between phosphorylated STAT3 (p-STAT3) and an endogenous phosphatase for targeted STAT3 dephosphorylation. Gold nanoclusters (GNCs) serve as a scaffold to conjugate STAT3-targeting peptides and protein tyrosine phosphatase non-receptor type 13 (PTPN13)-targeting peptides. Through precise optimization of the number and ratio of the two targeting peptides, TDNAs achieves more than 90% dephosphorylation of p-STAT3. In vivo studies further confirm that the TDNAs efficiently dephosphorylates p-STAT3 in tumor models within 24 h and activates antitumor immunity, thereby enhancing cancer immunotherapy. This study demonstrates the feasibility of inducing STAT3 dephosphorylation via proximity-based technology and provides a preclinical proof of concept for restoring STAT3 inactivity as a strategy for cancer immunotherapy.