Copper-Induced Cell Death Activates Immune System, May Help Overcome Immunotherapy Resistance

A preclinical study from researchers at The University of Texas MD Anderson Cancer Center, published today in Cell, details a connection between the immune system and cuproptosis, a type of copper-induced cell death. The findings suggest a new approach to help overcome resistance to immunotherapy.

The study, led by Boyi Gan, Ph.D., professor of Experimental Radiation Oncology, demonstrates that cancer cells undergoing cuproptosis release signals that activate the immune system. Significantly, this study is among the first to demonstrate that cuproptosis can actively engage the immune system and enhance responses to immunotherapy. In preclinical models, a combination approach of cuproptosis-inducing treatment along with anti-PD-L1 immunotherapy significantly slowed tumor growth.

“This study reveals a previously unrecognized partnership between the immune system and cuproptosis,” 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.”

What is cuproptosis and what is its relationship with the immune system?

Cuproptosis is a recently discovered type of regulated cell death that is triggered by excess copper. Some cancer cells appear especially sensitive to cuproptosis, making it an area of growing interest for therapy development. However, how the process interacts with the immune system has not been well understood.

This study identified a two-way interaction between immune cells and cuproptosis. In preclinical models, the presence of immune cells – specifically CD8-positive T cells, which play a key role in attacking cancer – had a significant impact on the anticancer effects of cuproptosis, and the process itself released signals that activated the immune system.

Together, these effects created a reinforcing cycle: immune cells promoted cuproptosis in cancer cells, and cuproptosis, in turn, stimulated stronger antitumor immune responses.

What is the potential for this discovery to overcome immunotherapy resistance?

While immunotherapy has transformed cancer treatment, many patients either do not respond or eventually develop resistance to it, creating an urgent need for new strategies that can restore immune sensitivity.

An especially notable finding from this study: combining an agent to induce cuproptosis with immune checkpoint inhibition was effective even in models that were resistant to immunotherapy on its own. The researchers also found that higher levels of the FDX1 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.