Reprogramming Immune-Cold Prostate Tumors Improves Therapeutic Response

Prostate cancer is often resistant to immunotherapy, which harnesses a person’s immune system to recognize and destroy tumors. But a new technology that targets RNA in cancer cells gave immune therapy new life, improving its ability to unleash cancer-killing cells in laboratory studies.

Most prostate tumors are dubbed “immune cold” because they don’t attract T cells (a type of immune cell) to the tumor. Using a CRISPR-based tool, researchers altered RNA to make the cancer cells more like magnets for T cells, allowing them to draw in and use the anti-tumor cells to destroy the cancer.

Published in Nature Biomedical Engineering, the study found the technology made prostate tumors more responsive to immune checkpoint therapy in mice, increasing the number of immune cells that infiltrated the tumor and subsequently destroyed cancerous 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 of the study from 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 and could be used in conjunction with existing immunotherapies in prostate and potentially other immune-cold tumor types.”

Why doesn’t immune therapy work in prostate cancer?

The research began 12 years ago, when Wagner’s team discovered that many mRNAs (messenger RNAs) were shorter than normal in glioblastoma (brain cancer) cells. Over time they and others found that mRNA shortening happens in all types of cancer and is likely a strategy that cancer cells use to evolve and evade treatment.

mRNA carries genetic instructions from DNA to the cell’s protein‑making machinery, which turns the information into proteins the body needs to function. When mRNAs are shorter, they are more stable: like animals that make themselves smaller for protection (think hedgehogs and pangolins), compact mRNAs with a smaller surface area are less likely to be “eaten” by enzymes present in cells. Short mRNAs are also more difficult for cells to manage and control, so they can spread unchecked. This means they stick around for longer and can produce more protein.

One way cancer becomes immune cold is through the destruction of the MHC-1 complex, which is like a magnet that draws immune cells to the tumor. Without MHC-1, T cells don’t recognize or kill malignant cells.

In the new study, scientists found:

• There is a specific protein (SPSB1) that destroys the MHC-1 complex.
• In prostate cancer, the mRNA that carries the instructions to create this protein is shortened. Consequently, it produces more protein.
• More SPSB1 protein means less of the MHC-1 complex.
• Less of the MHC-1 complex makes immune therapy futile, because there’s no magnet to attract T cells to the tumor.

CRISPR creates promise for immune cold cancers

The collaborative research team, led by scientists from Duke University School of Medicine, designed a first-of-its-kind therapy to change the length of the mRNA for the SPSB1 protein. Using an RNA-based CRISPR Cas13 system, they forced the SPSB1 mRNA to re-lengthen.

While CRISPR typically cuts RNA or DNA, they created a system that binds to, rather than cuts, a specific part of the mRNA. This binding blocked tumor cells from accessing and shortening the end, or tail, of the mRNA.

Allowing the mRNA to maintain its normal, longer length, led to less SPSB1 protein in the cells and restored the MHC-1 complex. And with the MHC-1 complex back online, immune checkpoint therapy was much more effective at combatting the cancer. The team conducted a thorough review of the data and didn’t identify any off-target effects of the novel CRISPR therapy.

“No one has ever done this before. It’s an excellent preclinical model showing that mRNAs can be forced to re-lengthen and when they do, there’s therapeutic benefit,” said Wagner, professor of Biochemistry and Biophysics and co-director of the Center for RNA Biology. “Cancer is super smart at evolving, but it's not a magician. If we can hit it with immunotherapy and another synergistic drug that pumps up the immune response, we could potentially cure it. It won’t be able to evolve fast enough.”

Reference: Huang F, Yuan F, Li K, et al. Programmable mRNA 3′UTR engineering restores MHC-I and overcomes immune evasion in prostate cancer. Nat Biomed Eng. 2026. doi: 10.1038/s41551-026-01720-9

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