Researchers at the University of North Carolina School of Medicine and the UNC Lineberger Comprehensive Cancer Center have identified a new way to help the immune system fight melanoma, the most lethal type of skin cancer. Their findings were published in the Journal of Clinical Investigation.
The research team found that by inhibiting a protein known as speckle-type POZ (SPOP), they could make immunotherapies and CAR T-cell therapy more effective against melanoma. This approach could potentially benefit patients with advanced stages of the disease, where traditional treatments such as surgery are not always an option and current therapies often have limited success rates.
“For the first time, we were able to confirm that this specific protein contributes to the growth of melanoma,” said Pengda Liu, PhD, a biochemist at UNC Lineberger Comprehensive Cancer Center. “We also showed that by manipulating this protein in melanoma models, we can bolster our immune cells’ ability to infiltrate solid tumors and enhance the efficacy of immunotherapies.”
Prior to this study, researchers did not know whether SPOP played any role in melanoma. The protein belongs to a family called E3 ubiquitin ligases, which have been linked to genetic mutations affecting cancer growth in other organs such as the prostate and kidneys.
Liu and Gianpietro Dotti, MD, professor of microbiology and immunology at UNC School of Medicine, discovered that SPOP enables tumors to avoid detection by the immune system. Their experiments using mouse models demonstrated that removing SPOP from tumors allowed for stronger attacks from immune cells, leading to smaller tumors.
Further investigation revealed that SPOP destabilizes an essential “immune sensor” called STING. STING detects harmful genetic material like viral infections or DNA damage and alerts the body’s defense mechanisms.
When Liu and Dotti’s teams used a small molecule inhibitor targeting SPOP, they observed not only stabilization but also further activation of STING through increased DNA damage. The inhibitor works by acting as molecular glue between SPOP and another protein called CBX4. This interaction leads to degradation of CBX4 and results in heightened DNA damage signals within tumor cells.
The research showed two key effects: SPOP inhibitors helped immune cells penetrate tumor defenses more effectively and improved CAR-T cell function against tumors.
Additionally, Liu’s group is developing new biomaterials for sustained release of therapeutic molecules—such as devices or patches—to deliver treatment without frequent injections or continuous IV infusions. “One day, we hope to develop a small device or an implantable patch so that patients don’t need to take pills or stay connected to IV bags for chemotherapy,” said Liu. “We just want to use whatever we can do to improve the therapy efficacy and quality of life for cancer patients.”
The study was led collaboratively by Zhichuan Zhu, PhD, and Xin Zhou, PhD—postdoctoral fellows from both labs—with Drs. Dotti and Liu serving as co–corresponding authors.
