New CRISPR Technology Boosts Immunotherapy Effectiveness in Prostate Cancer

Prostate cancer has traditionally been considered difficult to treat with immunotherapy—a method that activates the immune system to recognize and destroy tumors. Recently, researchers have developed an experimental RNA-targeting technology that can make prostate tumors more susceptible to immune attack.

Characteristics of Prostate Tumors

Most prostate tumors are classified as "immunologically cold" because they attract few T-cells, which are key players in the immune response. The low number of T-cells in these tumors makes immunotherapy largely ineffective. In laboratory studies using CRISPR-based tools, scientists modified RNA within prostate cancer cells, making the tumors more visible and attractive to immune cells. Results published in Nature Biomedical Engineering showed that this technology enhanced the tumors’ response to immune checkpoint therapy in mice: more immune cells infiltrated the tumors, attacking and destroying cancer cells.

Reasons for Immunotherapy Resistance

Research has shown that many mRNAs (messenger RNAs) in tumor cells are shorter than normal, a phenomenon seen in various cancer types that helps tumors adapt and survive. mRNA carries genetic instructions from DNA to the cell’s protein-making machinery. Shortened mRNAs are typically more stable and harder for the cell to regulate, allowing them to remain active longer and produce more protein without normal cellular control.

One reason tumors become immunologically cold is the loss of the MHC-1 complex—a molecular signal that helps T-cells recognize cancer cells. Without this complex, malignant cells become less detectable by the immune system.

The Mechanism Behind Immune Signal Suppression

In prostate cancer, shortened mRNA leads to increased production of the SPSB1 protein, which destroys the MHC-1 complex. Higher levels of SPSB1 reduce MHC-1, preventing T-cells from being drawn to the tumor and making immunotherapy ineffective.

Restoring the Immune “Magnet” with CRISPR

The research team developed a therapy that restores the normal length of the mRNA responsible for SPSB1 synthesis using the CRISPR Cas13 system, which targets RNA. This system attaches to a specific region of the mRNA and prevents it from being shortened, keeping the molecule in its longer form. As a result, SPSB1 protein levels decrease, allowing the MHC-1 complex to return to the cell surface. Once MHC-1 is restored, immune checkpoint therapy becomes much more effective against prostate tumors. No side effects from the experimental CRISPR treatment were observed during the analysis.

Future Prospects for the Technology

Currently, researchers are exploring the potential of this approach for other immunologically cold tumors, including pancreatic cancer, which also often responds poorly to immunotherapy. This research is funded by the Wilmot Cancer Institute and the Roswell Park Comprehensive Cancer Center. The study is also supported by the National Cancer Institute at the National Institutes of Health.