常陸 圭介

Small extracellular vesicles (sEVs) mediate cell-to-cell communication by carrying RNAs and proteins. Ubiquitin-like 3 (UBL3) functions as a posttranslational modification factor, regulating protein sorting to sEVs. Programmed cell death ligand 1 (PD-L1) binds to programmed cell death 1 (PD-1) on immune cells, suppressing their function. Although immune checkpoint inhibitors, anti-PD-L1 and anti-PD-1 antibodies, have improved cancer treatment, efficacy remains limited (~ 25%). Per recent studies, PD-L1-containing sEVs are elevated in cancer patients, contributing to impaired immunotherapy responses. Herein, we discovered that PD-L1 is modified by UBL3 and that its sorting to sEVs is regulated by UBL3. Furthermore, we found that statins, commonly prescribed for hypercholesterolemia, inhibit UBL3 modification, thereby reducing PD-L1 sorting to sEVs. Among patients with a high tumor proportion score, serum levels of PD-L1-containing sEVs were significantly lower in those using statins. Consistently, bioinformatic analysis revealed that UBL3 and PD-L1 expression levels affect lung cancer survival. Integrating statins into existing combination therapies may therefore offer a promising strategy to enhance immunotherapy efficacy.

Lower grade gliomas frequently harbor mutations in isocitrate dehydrogenase (IDH), which define biologically distinct tumor subtypes. Although IDH-mutant and IDH-wildtype gliomas share similar histological morphology, they display markedly different metabolic profiles that may be exploited for targeted therapy. In this study, we investigated therapeutic approaches tailored to these metabolic differences. Using capillary electrophoresis-mass spectrometry, we compared the metabolomes of engineered IDH-wildtype and IDH-mutant glioma cell models. IDH-mutant cells exhibited elevated asparagine levels and reduced glutamine and glutamate levels compared with IDH-wildtype cells. These differences were corroborated in vivo by proton magnetic resonance spectroscopy of 130 patients with diffuse gliomas, showing lower glutamine and glutamate in IDH-mutant tumors. Pharmacological depletion of asparagine with L-asparaginase, which converts asparagine to aspartate, preferentially inhibited the growth of IDH-wildtype glioma cells, and this effect was potentiated by inhibition of asparagine synthetase. In contrast, inhibition of glutamate dehydrogenase 1 (GLUD1), the enzyme catalyzing the conversion of glutamate to α-ketoglutarate, selectively suppressed proliferation of IDH-mutant glioma cells by inducing reactive oxygen species accumulation and apoptosis. In vivo, L-asparaginase suppressed tumor growth in xenografted IDH-wildtype gliomas, whereas GLUD1 inhibition significantly reduced tumor growth in IDH-mutant glioma xenografts. These findings reveal distinct amino acid metabolic vulnerabilities defined by IDH mutation status and identify L-asparaginase and GLUD1 inhibition (via R162) as promising, mutation-specific therapeutic strategies. L-asparaginase demonstrated potent antitumor activity against IDH-wildtype gliomas, while GLUD1 inhibition selectively suppressed IDH-mutant gliomas both in vitro and in vivo. These results highlight the clinical potential of targeting amino acid metabolism in gliomas and provide a strong rationale for translating these mutation-specific approaches into future clinical trials.