New Insight into Cancer-Related Cognitive Impairment to Improve Immunotherapy

New research enhances our understanding of the complex interplay among cancer, immunotherapy and brain health, potentially leading to improved treatments and better quality of life for cancer survivors.

Irvine, Calif., July 7, 2025 — Cancer can alter how the brain works, and modern treatment options that attack the disease can cause additional issues in the brain. Understanding how immunotherapies, or immune checkpoint inhibitors (ICIs), affect normal functions of the brain is important when it comes to improving the quality of life for millions of cancer survivors.

“We study mechanisms of cancer-related cognitive impairments,” says Munjal M. Acharya, PhD, an associate professor in the Department of Anatomy & Neurobiology in the UC Irvine School of Medicine. Working with Shivashankar Othy, PhD, an assistant professor in the Department of Physiology & Biophysics, has led to new insights into how ICIs work.

“ICIs rejuvenate the immune system to fight cancers,” says Othy, “but at the risk of dysregulating immune homeostasis in various organ systems, including the brain.”

Their collaborative study found not only that melanoma can alter how the brain works but also that ICIs can cause additional issues in the brain, even in mice without cancer.

“Our study addresses growing concern about cognitive and neurological side effects in cancer survivors who have undergone immunotherapy treatments,” says Acharya. Othy adds that, based on their findings, “we predict that identifying ways to selectively control the activation of brain immune cells called microglia might help reduce the brain-related side effects of immunotherapies while maintaining the beneficial effect of cancer treatment.”

The team of UC Irvine researchers outline their findings in a paper published in the Journal of Experimental & Clinical Cancer Research.

Examining Immune Checkpoint Inhibitors

Looking in particular at melanoma, the research team examined how ICI treatment affects learning, memory and other cognitive functions.

They found that ICIs affected synaptic connections in the brain, reduced protective coating (myelin) around nerve cells, and impaired the ability of mice to learn and remember. ICIs also activated microglia, increasing the number of reactive or damaging immune cells in the brain. These changes lasted several weeks after treatment ended.

“We also found that the ICI treatments predispose the brains of mice for autoimmune conditions such as multiple sclerosis (MS)-like disease,” says Othy. “These findings provide crucial insights into the long-term impact of ICIs, highlighting the importance of ongoing monitoring and care for cancer survivors.”

Acharya credits the multidisciplinary nature of the work and partnership with the Othy Laboratory for accelerating progress. “Dr. Othy’s background in neuroimmunology, advanced microscopy, T cell signaling and immune regulation complements our focus on cognition, neuroinflammation and microglial signaling,” he says. “This complimentary expertise helped us approach the research from multiple angles, creating a strong foundation for translating basic science findings into potential clinical applications.”

Developing Targeted Interventions

Identifying specific mechanisms through which ICIs affect brain function — such as microglial activation and synaptic damage — opens new avenues for developing targeted interventions to prevent or mitigate these side effects.

Both Acharya and Othy stress how understanding these side effects could lead to the development of strategies to maintain the effectiveness of cancer treatments while reducing neurological complications, improving overall patient outcomes and quality of life. “Despite the growing use of immunotherapies, their effects on the central nervous system were not well understood,” says Acharya.

“This research helps to fill that critical knowledge gap,” says Othy.

The study highlights the potential of targeting microglial activation to preserve brain function during cancer treatment, offering a clear direction for future research and drug development.

Next steps include conducting clinical studies to verify if these findings translate to individuals who received ICI treatments, as well as developing interventions to better protect the brain during treatment. Researchers could also search for biomarkers that might predict which patients are more susceptible to neurological side effects from ICI treatments.

“Our findings suggest that targeting microglial activation could be a strategy to preserve brain function during cancer treatment,” says Acharya. “Furthermore, our focus on long-term effects helps in developing precision health approaches for cancer survivors, potentially leading to personalized long-term monitoring and intervention plans. It contributes to the goal of delivering the right treatment to the right patient at the right time while minimizing adverse effects.”