A research team from Fujita Health University in Japan, along with collaborators from Tokyo Medical University and Tokyo Medical University Hospital, has identified a new mechanism that may help improve the effectiveness of immune checkpoint inhibitors used in cancer immunotherapy. The study, published in Scientific Reports on December 15, 2025, focuses on how tumors evade immune responses by releasing small extracellular vesicles (sEVs) containing PD-L1, a protein known to suppress immune function.
"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." This question guided the researchers' investigation.
The team used a combination of molecular biology techniques and patient-derived samples to identify ubiquitin-like 3 (UBL3) as a key factor controlling how PD-L1 is incorporated into sEVs. They found that UBL3 modifies PD-L1 through a specific chemical bond at cysteine 272 in its cytoplasmic domain. When UBL3 was overexpressed in cells, more PD-L1 appeared in sEVs; when UBL3 was reduced, less PD-L1 was found in these vesicles.
One notable finding was that statins—drugs commonly prescribed to lower cholesterol—can inhibit the activity of UBL3. The study showed that all clinically used statins suppressed UBL3’s modification of PD-L1 and decreased its presence in sEVs at concentrations achievable with standard medical doses. Analysis of blood samples from non-small cell lung cancer patients indicated that those taking statins had lower levels of circulating PD-L1-containing sEVs if their tumors expressed high levels of PD-L1.
Further bioinformatic analysis suggested that higher combined expression levels of UBL3 and PD-L1 were linked to survival outcomes among lung cancer patients. The authors believe this regulatory pathway could explain why many patients do not respond well to current immune checkpoint inhibitors.
"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."
The findings suggest that using statins alongside existing immunotherapies could be an affordable way to overcome some forms of resistance seen with current treatments for cancer.
