Scientists Discover Why Immunotherapy Frequently Fails

Although cancer immunotherapy has transformed treatment for many patients, the promise of effective immunotherapy falls short for many patients. Scientists now believe they have identified a major reason why immunotherapy isn’t always effective. 

New research shows that cancer cells rely on a previously hidden escape route to weaken immune attacks, and a class of widely used medications may help block it. The study, led by Professor Kunihiro Tsuchida at Fujita Health University, suggests that cancer cells do more than evade immune checkpoints. 

They actively distribute immune-suppressing signals throughout the body, reducing the effectiveness of immunotherapy even when tumors appear responsive based on standard markers. 

Immunotherapy drugs such as PD-1 and PD-L1 inhibitors work by releasing the restraints tumors place on immune cells. This results in long-term tumor control in some patients while in many others, immune activity never fully recovers. According to Professor Tsuchida, the issue is often not immune cell failure, but the way cancer extends immune suppression beyond the tumor itself. 

Researchers examined tiny particles known as small extracellular vesicles: microscopic structures that are released by cancer cells and circulate through the bloodstream. They contain PD-L1, the same immune-blocking protein targeted by checkpoint inhibitors. Once dispersed, these vesicles can suppress immune responses far from the tumor, limiting treatment impact. A central finding was uncovering how PD-L1 is directed into these vesicles. 

The team identified a lesser-known protein, UBL3 (ubiquitin-like 3), that functions as a regulatory switch. Rather than increasing PD-L1 production, UBL3 determines whether the protein is packaged and exported out of the cell. 

Professor Tsuchida explained that PD-L1 undergoes a newly identified chemical modification that depends on UBL3. When UBL3 activity rises, more PD-L1 is loaded into vesicles and released into circulation. When UBL3 is inhibited, that export process slows substantially while PD-L1 levels inside the cell remain unchanged. 

An unexpected result emerged during efforts to disrupt this pathway. The researchers found that statins, commonly prescribed cholesterol-lowering drugs, significantly reduced UBL3 activity. 

Every statin tested interfered with PD-L1 packaging, resulting in far fewer immune-suppressing vesicles entering circulation.  Crucially, this effect occurred at standard therapeutic doses and without damaging cells. Blood samples from individuals with non-small cell lung cancer supported the laboratory findings. 

Patients already taking statins showed notably lower levels of PD-L1-carrying vesicles in their bloodstream, especially when tumors exhibited high PD-L1 expression. 

The findings carry important implications for cancer treatment as they help explain why immunotherapy can fail even when tumors meet established criteria for treatment. It also highlights a practical way to improve outcomes using medications that are inexpensive, well understood, and widely prescribed. 

Statins could be used to reinforce immunotherapy rather than replace it. By limiting a cancer cell’s ability to spread immune suppression throughout the body, the immune system may finally gain a more even footing against cancerous cells, potentially improving responses for patients who currently see little benefit from checkpoint inhibitors. 

These findings are likely to be of great interest to entities like Calidi Biotherapeutics Inc. (NYSE American: CLDI) that are engaged in developing immunotherapies against cancer. 

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