Protein Balance Found to Be Key to Overcoming Cancer Immunotherapy Resistance

Immunotherapy, which harnesses the body’s immune system to combat cancer, includes treatments such as immune checkpoint inhibitors. These inhibitors work by blocking certain proteins that would otherwise slow the immune response, allowing immune cells to attack cancer cells more effectively. Despite their promise, most patients either do not respond well to checkpoint inhibitors or develop resistance over time. 

In a study published in Nature, researchers at the University of Michigan found that the interplay between two proteins, STAT3 and STAT5, is crucial in determining how tumors respond to immune checkpoint therapy. According to senior author Weiping Zou, “Resistance to cancer immunotherapy is a huge issue for cancer patients. That’s why it’s important to understand the underlying mechanisms and figure out how to deal with this problem.”

Comparing the immune system to a military unit, Zou explains that T cells act as soldiers targeting tumor cells, while dendritic cells function as generals, directing the immune response. Dendritic cells activate T cells by presenting them with abnormal proteins from tumors. Analysis of RNA sequencing data from cancer patients revealed that STAT3 and STAT5 together regulate the number of dendritic cells. Patients who responded to checkpoint inhibitors had higher STAT5 and lower STAT3 signaling.

Using mouse models, the researchers demonstrated that STAT3 inhibits the maturation of dendritic cells and the activation of T cells, counteracting STAT5. This mechanism was observed in various tumor types, including skin, ovary, breast, lung, and colon cancers. Co-author Shaomeng Wang, noted, “Although researchers have known that STAT3 is a cancer target for many years, these results uncovered a previously unknown mechanism of immune checkpoint resistance.”

To address this, the team used the body’s protein degradation system to target STAT3. They developed two molecules, SD-36 and SD-2301, which degraded STAT3 in dendritic cells, enhancing immunity and STAT5 signaling. Both molecules proved effective in treating advanced and resistant tumors in preclinical models. The researchers plan to begin clinical trials to assess the potential of these STAT3 degraders in cancer therapy.