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.

BACKGROUND: The inferior alveolar nerve (IAN) may be injured during extraction of the mandibular third molar, causing severe postoperative complications. Many methods have been described for evaluating the relative position between the mandibular third molar and the inferior alveolar canal (IAC) on panoramic radiography and computed tomography, but conventional radiography provides limited information on the proximity of these two structures. The present study assessed the benefits of three-dimensional computed tomography (3D-CT) prior to surgical extraction of the mandibular third molar, to prevent IAN damage. METHODS: This retrospective study included 4917 extractions in 3555 patients who presented for extraction of the mandibular third molars. The cases were classified into three groups, according to anatomical relationship between the mandibular third molars and the IAC on panoramic radiography and whether 3D-CT was performed. Symptoms of IAN damage were assessed using the touch-recognition test. Data were compared using the chi-square test and Fisher's exact test. RESULTS: Among the 32 cases of IAN damage, 6 cases were included in group I (0.35 %, n = 1735 cases), 23 cases in group II (1.1 %, n = 2063 cases), and 3 cases in group III (0.27 %, n = 1119 cases). The chi-square test showed a significant difference in the incidence of IAN damage between groups I and II. No significant difference was observed between groups I and III using Fisher's exact test. In the 6 cases of IAN damage in group I, the mandibular third molar roots were located lingual relative to the IAC in 3 cases and middle relative to the IAC in 3 cases. The overlap was > or =2 mm in 3 of 6 cases and 0-2 mm in the remaining 3 cases. The mean distance between the mandibular third molar and IAC was 2.2 mm, the maximum distance 12 mm, and the minimum distance 0.5 mm. Greater than 80 % recovery was observed in 15 of 32 (46.8 %) cases of IAN damage. CONCLUSIONS: 3D-CT may be a useful tool for assessing the three-dimensional anatomical relationship and proximity between the mandibular third molar and IAC in order to prevent IAN damage during extraction of mandibular third molars.
Humans ; Incidence ; Mandibular Nerve* ; Molar, Third* ; Postoperative Complications ; Radiography ; Radiography, Panoramic ; Retrospective Studies ; Tomography, Spiral Computed ; Tooth Extraction