A type of therapy called spliceosome inhibitors could help “turn cold tumors hot,” making small cell lung cancer — one of the hardest cancers to treat — more responsive to immunotherapy.
The drugs don’t just kill cancer cells directly, they also target surrounding fibroblasts, making tumors more responsive to the immune system.
In mouse models, combining a spliceosome inhibitor with immunotherapy made tumors shrink dramatically.
PHILADELPHIA (November 24, 2025) — For more than a decade, a class of drugs called spliceosome inhibitors has been studied as a strategy for killing cancer cells. Now, new research by Fox Chase Cancer Center scientists suggests that these drugs may be more effective as a tool to supercharge immunotherapy, drugs that harness the power of the body’s immune system, in small cell lung cancer.
The paper shows, for the first time, that spliceosome inhibitors affect noncancerous cells within the tumor microenvironment, including fibroblasts, helping the immune system recognize and fight the tumor more effectively. The tumor microenvironment comprises noncancerous cells and other components that surround tumor cells.
“What we now propose is that we can use spliceosome inhibitors not only to kill cancer cells, but also to target cells in the tumor microenvironment, like fibroblasts,” said Israel Cañadas, PhD, Assistant Professor in the Nuclear Dynamics and Cancer Research Program and the Cancer Epigenetics Institute at Fox Chase.
The findings are especially exciting for a disease like small cell lung cancer because it’s a so-called “cold” tumor, meaning it is unresponsive to immune cells. That makes immunotherapy ineffective and means that the cancer is highly resistant to current treatments.
The hope is that spliceosome inhibitors could help turn these cold tumors “hot,” potentially making them treatable.
How Spliceosome Inhibitors Work
Spliceosome inhibitors block the process of RNA splicing, which is an important step in the proliferation of cancer cells. Previous research showed that blocking this step kills cancer cells. More recent studies have found that spliceosome inhibitors also activate an immune response. The new Fox Chase study helps explain why.
Key Findings
Viral mimicry: Small cell lung cancer and noncancerous cells treated with a spliceosome inhibitor accumulated Z-RNA, a special form of double-stranded RNA that mimics a viral infection, triggering an immune response.
Cell death: Treated cells died by necroptosis, a type of inflammatory cell death. This occurred in both cancer and fibroblast cells.
Tumor reduction: When mice with small cell lung cancer were given the drug, their tumors shrank significantly. The tumors showed the presence of disease-fighting immune cells.
Better together: When the spliceosome inhibitor was combined with an immunotherapy drug, tumors shrank even more.
Potential biomarker: Spliceosome inhibitors were only effective in mice that expressed a protein called ZBP1, making it an attractive biomarker for identifying which tumors might be most susceptible to treatment.
Strategies for Hard-to-Treat Cancers
Small cell lung cancer is the most aggressive and deadly form of lung cancer, with few treatment options. Cañadas’ lab has focused on strategies for making “cold” tumors like small cell lung cancer more capable of producing an immune response.
“We think the concept of viral mimicry is a very efficient way to make that happen,” he said. Next, the team plans to continue their research in a patient-derived organoid model, testing spliceosome inhibitor drugs in small cell lung cancer tumor tissue taken from human patients.
The study, “Spliceosome Inhibition Induces Z-RNA and ZBP1-Driven Cell Death in Small Cell Lung Cancer,” was published in Cell Reports.