Researchers in Japan have uncovered how cancer cells use tiny vesicles to spread the immune-suppressing protein PD-L1, explaining why immunotherapy often fails. A protein called UBL3 directs this process, but common statins can disrupt it, potentially boosting treatment effectiveness. The findings, from patient samples and lab tests, suggest a simple way to improve outcomes for lung cancer patients.
Cancer immunotherapy, which harnesses the immune system to fight tumors, has transformed treatment for some patients through drugs targeting the PD-1/PD-L1 pathway. However, many tumors evade these therapies by releasing small extracellular vesicles (sEVs) loaded with PD-L1, an immunosuppressive protein that dampens immune responses body-wide.
A team led by Professor Kunihiro Tsuchida at Fujita Health University, in collaboration with Tokyo Medical University Hospital and Tokyo Medical University, investigated this mechanism. Published in Scientific Reports in 2025, their study revealed that ubiquitin-like 3 (UBL3) is crucial for sorting PD-L1 into sEVs. This involves a unique post-translational modification via a disulfide bond at cysteine 272 in PD-L1's cytoplasmic region, distinct from standard ubiquitination.
Experiments showed that elevating UBL3 increased PD-L1 packaging in sEVs without altering total cellular PD-L1 levels, while depleting UBL3 reduced it. Strikingly, statins—widely used cholesterol-lowering drugs—interfered with UBL3 modification at low, clinically relevant doses, slashing PD-L1 in sEVs without toxicity.
Cancer cells release small extracellular vesicles containing PD-L1, which are thought to reduce the effectiveness of cancer immunotherapy. However, how PD-L1 is sorted into these vesicles has remained unclear.
In non-small cell lung cancer patients with high tumor PD-L1, those on statins had significantly fewer PD-L1-laden sEVs in their blood than non-users. Bioinformatics linked UBL3 and PD-L1 expression to survival in lung cancer.
In the long term, this research may lead to more effective and accessible cancer immunotherapies. It could help more patients benefit from immune checkpoint treatments, improving survival and quality of life in real-world settings.
This discovery highlights a targetable immune escape route, suggesting statins could enhance checkpoint inhibitors affordably, given their safety and availability.
