Prostate cancer, long the bane of immunotherapists everywhere, has finally shown a chink in its armor thanks to a new RNA-targeting CRISPR tool. Most prostate tumors are considered 'immune cold,' meaning they attract about as many T cells as a January beach party. But researchers have now developed a way to make these tumors visible to the immune system, effectively turning up the heat.

In a study published in Nature Biomedical Engineering, scientists used a CRISPR-based system to force prostate cancer cells to re-lengthen shortened mRNA molecules - a trick tumors use to hide from immune attack. By restoring the normal length of a key mRNA, the therapy reduced production of the SPSB1 protein, which in turn allowed the MHC-1 complex (think of it as a molecular 'Kick Me' sign for T cells) to reappear on the tumor surface. The result? Immune checkpoint therapy suddenly worked much better in mice, with more immune cells storming the tumor and destroying cancer cells.

'Immune therapy is a monumentally different way to treat cancer, and a great way because you don't have to give patients terrible drugs that kill the cancer but harm healthy cells in the process,' said Eric J. Wagner, PhD, co-author from the University of Rochester Medicine. 'The problem is that some cancers respond well to immune therapy, but others develop resistance or don't respond at all. Our tool strengthens the immune system's ability to make the cancer go away.'

The research builds on a discovery made 12 years ago, when Wagner's team found that mRNAs in glioblastoma cells were shorter than normal. Shortened mRNAs are more stable - like a hedgehog curling into a ball - and harder for cells to regulate. In prostate cancer, this shortening messes with the MHC-1 complex, allowing tumors to fly under the immune radar.

The team, led by Duke University School of Medicine, engineered a CRISPR Cas13 system that binds to a specific section of the SPSB1 mRNA instead of cutting it. This prevented cancer cells from shortening the tail of the molecule. 'No one has ever done this before,' Wagner said. 'It's an excellent preclinical model showing that mRNAs can be forced to re-lengthen and when they do, there's therapeutic benefit.'

No off-target effects were detected, which is nice. Wagner now plans to test the approach in pancreatic cancer, another notoriously cold tumor, with pilot funding from Wilmot Cancer Institute and Roswell Park Comprehensive Cancer Center. The research was funded by the National Cancer Institute at the National Institutes of Health.