Cancer immunotherapy has reshaped cancer treatment by training the body's immune system to recognize and attack tumors. Drugs known as immune checkpoint inhibitors, which target the PD-1/PD-L1 pathway, have led to long-lasting responses in some patients and fueled optimism about durable cancer control. Yet for most people, these therapies do not deliver the same benefit. Tumors can adapt and develop ways to escape immune detection, limiting the effectiveness of treatment.
This challenge has pushed researchers to look beyond the tumor itself and examine broader mechanisms of immune resistance. Scientists are increasingly focused on how cancers suppress immune activity throughout the body, not just at the tumor site. One emerging area of interest involves small extracellular vesicles (sEVs), tiny particles released by cancer cells that can carry immunosuppressive molecules and weaken the immune response in ways that are still not fully understood.
Investigating How PD-L1 Is Packaged and Released
To better understand this process, a research team from Fujita Health University in Japan, led by Professor Kunihiro Tsuchida, worked with collaborators from Tokyo Medical University Hospital and Tokyo Medical University. Their goal was to uncover how PD-L1, a key immune checkpoint protein, is selectively loaded into sEVs and to determine whether this pathway could be targeted therapeutically.
The study, published in Scientific Reports, was built around a central unanswered question. "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." Addressing this mystery became the foundation of the research.
A New Molecular Player in Immune Resistance
Using a wide range of techniques, including molecular and cell biology, biochemical and pharmacological tests, patient-derived samples, and bioinformatics, the researchers identified ubiquitin-like 3 (UBL3) as a key factor controlling how PD-L1 is directed into sEVs.
They found that PD-L1 undergoes a previously unknown post-translational modification involving UBL3. This modification occurs through a disulfide bond and differs from the classical process of ubiquitination. Further experiments showed that a specific amino acid, cysteine 272 in the cytoplasmic region of PD-L1, is essential for this modification.
When UBL3 levels were increased in cancer cells, the amount of PD-L1 packaged into sEVs rose sharply, even though total PD-L1 inside the cells remained unchanged. In contrast, reducing UBL3 levels led to a clear drop in PD-L1 being loaded into vesicles and released outside the cell. Together, these results confirmed that UBL3 plays a central role in directing PD-L1 into sEVs.
Statins Interfere With a Key Immune Escape Pathway
One of the most striking findings came when the team examined drugs that might interfere with this process. They discovered that statins, which are widely prescribed to lower cholesterol, strongly block UBL3 modification. All clinically used statins tested in the study reduced UBL3 activity, lowered PD-L1 modification, and sharply decreased the amount of PD-L1 sorted into sEVs.
These effects occurred at very low drug concentrations that are achievable in patients and were not linked to toxic effects on cells. Importantly, blood samples from people with non-small cell lung cancer showed a similar pattern. Among patients with high tumor PD-L1 expression, those taking statins had significantly lower levels of PD-L1-containing sEVs in their blood compared with patients not using statins.
Further bioinformatic analysis revealed that the combined expression of UBL3 and PD-L1 was associated with survival outcomes in lung cancer patients. This finding highlights the potential clinical importance of this newly identified regulatory pathway.
What This Means for Cancer Treatment
Taken together, these results help explain why immune checkpoint inhibitors often fail and point to a practical way to improve their performance. The study uncovers a hidden mechanism by which cancer cells spread immunosuppressive PD-L1 through extracellular vesicles, allowing tumors to weaken immune responses far beyond their immediate environment.
Linking this pathway to statins is especially important because these drugs are widely used, inexpensive, and generally safe. This raises the possibility that the findings could be translated into clinical practice relatively quickly. As the researchers note, "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."
A New Target for Overcoming Immunotherapy Resistance
In summary, the study shows that UBL3-driven modification promotes the packaging of PD-L1 into sEVs and that statins can disrupt this process, reducing levels of circulating immunosuppressive PD-L1. By identifying vesicle-associated PD-L1 trafficking as a modifiable driver of immune escape, the research opens a promising new path for tackling resistance to cancer immunotherapy. Adding statins to combination treatment strategies could offer a simple, scalable way to improve outcomes for patients receiving immune checkpoint inhibitors.
