LAMP2-Mediated Autophagy Plasticity Deters Lysosomal Uptake of Platinum Ions to Reverse Cisplatin-Induced Glioma Progression in a Macrophage Dependent Manner

Glioblastoma Multiforme (GBM) is the most common aggressive primary brain malignancy, with unsatisfactory overall survival. The role of lysosomal function, including autophagy, in GBM cisplatin resistance is critical for its continuous application in clinical practice. However, how they promote antitumor immunity in tumors and macrophages is poorly understood, and the underlying mechanisms are elusive. In this medicinal study, by exploring naphthalimide-Pt­(IV) complexes, named NTCDI-Pt, we demonstrated that in opposite to cisplatin, glioma cells treated with NTCDI-Pt decreased lysosome abundance to restrain platinum ions uptake in lysosomes by regulating Transcription Factor EB (TFEB) nucleus translocation, which finally caused more platinum ions accumulation in nucleus. What’s more, NTCDI-Pt polarized tumor-associated macrophages (TAMs) through triggering glioma cells release more HMGB1. Taken together, this study reveals the crucial strategies of regulating lysosomal function and cytoprotective autophagy to rescue platinum ions accumulation in nucleus for clinical application in glioma therapy.