Researchers at the Icahn School of Medicine at Mount Sinai and the Mount Sinai Tisch Cancer Center announced on Mar. 18 that they have identified a biological pathway that may explain why some bladder cancers do not respond well to immunotherapy. Their findings, published in Cancer Discovery, show that certain inflammation markers in the blood are connected to immune cells within tumors that can block the body's ability to fight cancer.
This discovery is significant because it links systemic inflammation in the blood with immune suppression inside tumors, offering new insight into why some patients fail to benefit from immunotherapy treatments for bladder cancer. Immunotherapy has improved outcomes for many patients, but doctors have struggled to understand why responses vary widely.
The research team found that high levels of C-reactive protein (CRP) and interleukin-6 (IL-6), both markers of inflammation in the blood, are associated with a specific group of immune cells called SPP1+ macrophages inside tumors. These macrophages can suppress T cells, which are crucial for attacking cancer cells. As a result, drugs known as immune checkpoint inhibitors may be less effective when these conditions are present.
"Immune checkpoint inhibitors have changed how we treat bladder cancer, but many patients do not have long-lasting responses," said Nina Bhardwaj, MD, PhD, Director of Immunotherapy and Ward-Coleman Chair in Cancer Research at Icahn School of Medicine at Mount Sinai. "We found that common blood markers like CRP and IL-6 are not just general signs of inflammation. They reflect a specific immune process inside the tumor that may block treatment."
The scientists used advanced genetic tools to analyze tumor samples and created what they describe as the largest single-cell atlas of bladder tumors so far. They also combined this data with RNA sequencing from multiple patient groups treated with immunotherapy. The study revealed another type of macrophage marked by CXCL9 that helps activate T cells and is linked to stronger immune responses.
"Our study shows that systemic inflammation can provide insight into what is happening inside tumors," said Diego Chowell, PhD, Assistant Professor at Icahn School of Medicine. "Inflammatory signals in the blood reflect specific immune programs that suppress T cells and limit the effectiveness of immunotherapy."
Matthew Galsky, MD, Director of Genitourinary Medical Oncology at Mount Sinai Tisch Cancer Center, said: "For clinicians, these results suggest that commonly used blood tests may provide insight into what is happening inside a patient's tumor before treatment begins. This framework may help identify patients who are more likely to have resistance to immunotherapy and support testing new combination treatment strategies." The findings also support ongoing clinical trials studying drugs targeting IL-6 signaling alongside immunotherapy.
The research team plans further studies on SPP1+ macrophages to better understand their role in suppressing the immune system and how future therapies might target or reprogram them.
