Copper-Induced Cell Death Activates Immune System, Offering New Strategy to Overcome Immunotherapy Resistance
Key Insights
A preclinical study from MD Anderson Cancer Center reveals that cuproptosis (search), a copper-induced form of cell death, can actively engage the immune system and enhance antitumor responses.
Researchers identified a reinforcing two-way interaction in which CD8-positive T cells (search) promote cuproptosis (search) in cancer cells, and cuproptosis in turn stimulates stronger immune responses.
Combining cuproptosis (search)-inducing agents with anti-PD-L1 immunotherapy (search) significantly slowed tumor growth, even in models resistant to immunotherapy alone.
A preclinical study from researchers at The University of Texas MD Anderson Cancer Center, published today in Cell, has uncovered a previously unrecognized link between the immune system and cuproptosis (search) — a recently discovered form of copper-induced regulated cell death. The findings suggest a promising new strategy to help overcome resistance to immunotherapy, a persistent challenge in oncology.
The study, led by Boyi Gan, Ph.D., professor of Experimental Radiation Oncology, demonstrates that cancer cells undergoing cuproptosis (search) release signals that activate the immune system. This research is among the first to show that cuproptosis can actively engage the immune system and enhance responses to immunotherapy. In preclinical models, a combination of cuproptosis-inducing treatment and anti-PD-L1 immunotherapy (search) significantly slowed tumor growth.
"This study reveals a previously unrecognized partnership between the immune system and cuproptosis (search)," Gan said. "Importantly, because the cuproptosis-inducing agents used in our studies already have clinical experience and favorable safety profiles, these findings may offer a practical path toward developing new combination treatments for patients whose cancers no longer respond to immunotherapy."
A Two-Way Interaction Between Immune Cells and Cuproptosis
Cuproptosis (search) is triggered by excess copper, and some cancer cells appear especially sensitive to this form of cell death, making it an area of growing interest for therapy development. Until now, however, how the process interacts with the immune system has not been well understood.
The study identified a bidirectional interaction between immune cells and cuproptosis (search). In preclinical models, the presence of immune cells — specifically CD8-positive T cells (search), which play a key role in attacking cancer — had a significant impact on the anticancer effects of cuproptosis. At the same time, the process itself released signals that activated the immune system.
Together, these effects created a reinforcing cycle: immune cells promoted cuproptosis (search) in cancer cells, and cuproptosis, in turn, stimulated stronger antitumor immune responses.
Overcoming Immunotherapy Resistance
While immunotherapy has transformed cancer treatment, many patients either do not respond or eventually develop resistance, creating an urgent need for new strategies that can restore immune sensitivity.
An especially notable finding from the study was that combining a cuproptosis (search)-inducing agent with immune checkpoint inhibition proved effective even in models that were resistant to immunotherapy on its own. The researchers also found that higher levels of the FDX1 (search) gene, which helps determine how susceptible cancer cells are to cuproptosis, were linked to better treatment responses. This gene could potentially serve as a biomarker to help identify patients most likely to benefit from this strategy.