Jang, Yeongji Choi, Jiwoong Park, Byeongmin Park, Jung Yeon Lee, Jae-Hyeon Goo, Jagyeong Shin, Dongwon Kim, Sun Hwa Kim, Yongju Song, Hyun Kyu Park, Jooho Kim, Kwangmeyung Yang, Yoosoo Shim, Man Kyu 2025-07-08T08:00:15Z 2025-07-08T08:00:15Z 2025-07-03 2025-09 2211-3835 https://pubs.kist.re.kr/handle/201004/152731 In light of the burgeoning successes of cancer immunotherapy, glioblastoma (GBM) remains refractory due to an immunosuppressive microenvironment originating from its molecular heterogeneity. Thus, identifying promising therapeutic targets for treating GBM and discovering methodologies to effectively regulate them is still a tremendous challenge. Here we describe photodynamic protein tyrosine phosphatase 1B (PTP1B) proteolysis mediated by a proteolysis-targeting chimera (PROTAC) nanoassembly. The PTP1B-targeting PROTAC is conjugated with a photosensitizer via a cathepsin B (Cat B)-cleavable peptide, which spontaneously forms nanoassemblies due to intermolecular π？π stacking interactions. In GBM models, PROTAC nanoassemblies significantly accumulate in the tumor region across the disrupted blood？brain barrier (BBB), triggering a burst release of the photosensitizer and active PROTAC by Cat B-mediated enzymatic cleavage. Upon laser irradiation, photodynamic therapy (PDT) synergizes with PROTAC-mediated PTP1B proteolysis to induce potent immunogenic cell death (ICD) in tumor cells. Subsequently, persistent PTP1B degradation by nanoassemblies in Cat B-overexpressed intratumoral T cells downregulates exhaustion markers, reinvigorating their functionality. These sequential processes of photodynamic PTP1B proteolysis ultimately augment T cell-mediated antitumor immunity as well as protective immunity, completely eradicating the primary GBM and preventing its recurrence. Overall, our findings underscore the therapeutic potential of combining PDT with PROTAC activity for GBM immunotherapy. English Elsevier BV Activatable PROTAC nanoassembly for photodynamic PTP1B proteolysis enhances glioblastoma immunotherapy Article 10.1016/j.apsb.2025.06.028 1 Acta Pharmaceutica Sinica B, v.15, no.9, pp.4886 - 4899 Acta Pharmaceutica Sinica B 15 9 4886 4899 Y scie scopus 001586154200026 Pharmacology & Pharmacy Pharmacology & Pharmacy Article Proteolysis-targeting chimera Targeted protein degradation Prodrug Supramolecular assembly Protein tyrosine phosphatase 1B Photodynamic therapy Nanomedicine Cancer immunotherapy