Abstract BACKGROUND Medulloblastoma (MB) is a central nervous system (CNS) tumor that predominantly affects children and always requires aggressive therapy. Affected individuals often suffer from treatment-related side effects, and treatment-resistant recurrences associated with high morbidity and mortality rates are common. There are four major molecular MB subgroups: wingless-type (Wnt)-activated, sonic hedgehog (Shh)-activated, group III (G3), and group IV (G4), where G3 MB is the most aggressive subgroup. MATERIAL AND METHODS In vivo, HLX-deleted G3 MB cells injected into mouse cerebella produce smaller tumors than those derived from parental cells. We have demonstrated that HLX modulates oxidative phosphorylation and mitochondrial dysfunction, and HLX overexpression downregulates genes encoding components of the electron transport chain (ETC), thereby potentially influencing HLX-induced G3 MB formation. RESULTS We have demonstrated that the H2.0-like homeobox transcription factor (HLX) is significantly upregulated in G3 MB cell lines and patient samples, implicating it in the development of G3 MB and suggesting it as a potential therapeutic target. HLX regulates MYC and IGF2BP3, which are known oncogenes in G3 MBs. We have developed B7-H3 (mAb) CAR-T exosomes carrying LNP-si-HLX that cross the blood-brain barrier (BBB), inhibit HLX in tumor cells, and modulate the tumor immune microenvironment. CONCLUSION Compared to cell-based immunotherapy, the anti-B7-H3/LNP-si-HLX-CAR-T exosomes further pique our interest in a novel and promising treatment strategy. Our study presents a novel paradigm for delivering targeted therapeutics and inducing specific anti-tumor immune responses within the tumor microenvironment.
Perera et al. (Wed,) studied this question.
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