A new combination therapy shows promise in treating “cold” cancers like prostate cancer, which are typically resistant to immunotherapy. By blocking the IRE1 signaling pathway, researchers have found a way to make these tumors susceptible to checkpoint inhibitors.

Immunotherapy is a revolutionary cancer treatment that harnesses the body’s own immune system to fight cancer cells. Unlike traditional treatments like radiation, surgery, and chemotherapy, which directly target cancer cells, immunotherapy focuses on manipulating the immune system within the tumor microenvironment.

The tumor microenvironment is a complex ecosystem containing cancer cells and various normal cells, including immune cells. While the immune system is designed to eliminate unwanted cells, it also has built-in brakes called checkpoints to prevent it from attacking healthy cells. Cancer cells can exploit these checkpoints to evade immune destruction, effectively keeping the brakes on the immune system.

Checkpoint inhibitors are drugs that release these brakes, allowing immune cells to attack cancer cells. This approach has been successful in treating certain types of cancer, extending lifespans significantly. However, some cancers, termed “cold tumors,” remain unresponsive to checkpoint inhibitors. These include pancreatic, ovarian, breast, and prostate cancers.

Researchers at the University of Oslo have made a significant breakthrough in overcoming immunotherapy resistance in prostate cancer. They discovered that blocking the IRE1 signaling pathway, which helps cells manage stress, could potentially transform cold tumors into hot ones, making them vulnerable to checkpoint inhibitors.

IRE1 is present in all cells, including cancer cells. Using a technique called single-cell RNA sequencing, the researchers observed that blocking IRE1 in prostate tumors reduced immunosuppressive effects in the microenvironment. This led them to hypothesize that blocking IRE1 could enhance the effectiveness of checkpoint inhibitors in prostate cancer treatment.

Their hypothesis proved correct. When they combined a checkpoint inhibitor with an IRE1 blocker (MKC8866), they observed a dramatic reduction in tumor growth in multiple mouse models.
Moreover, the composition of immune cells in the tumor microenvironment shifted towards an increase in cancer-killing immune cells.
While these findings primarily focus on prostate cancer, there’s reason to believe that this approach could benefit other cold tumors. IRE1 signaling is present in all cells, including other types of cancer cells. Studies suggest that the findings from this research may be applicable to other cold tumor types as well.

The next crucial step is to conduct clinical trials to evaluate the safety and efficacy of this combination therapy in human patients. If successful, this breakthrough could offer new hope for individuals with cold tumors who currently have limited treatment options.

Source.