A protein long known for its role in blood cell production has been unmasked as a master regulator of immune response in cancer, offering a potential game-changer for previously untreatable liver tumors.
In a stunning reversal of scientific expectations, researchers at Stanford Medicine have discovered that erythropoietin (EPO) – identified nearly 40 years ago for stimulating red blood cell production – actually plays a critical role in suppressing the immune system’s ability to fight cancer.
The groundbreaking study, published April 24 in Science, reveals that blocking EPO transforms formerly immune-resistant “cold” liver tumors in mice into “hot” tumors filled with cancer-fighting immune cells. When this approach was combined with existing immunotherapy, the results were remarkable.
“This is a fundamental breakthrough in our understanding of how the immune system is turned off and on in cancer,” said Edgar Engleman, MD, PhD, a professor of pathology and of medicine at Stanford and senior author of the research. “I could not be more excited about this discovery, and I hope treatments that target the mechanism we uncovered will quickly move forward to human trials.”
The findings solve a mystery that has puzzled cancer researchers for over a decade. In 2007, the FDA required a black box warning on EPO drugs cautioning against their use in cancer patients after studies showed they accelerated tumor growth. Until now, scientists couldn’t explain why.
The research team, led by basic life research scientist David Kung-Chun Chiu, PhD, discovered that in “cold” tumors, cancer cells produce and secrete EPO, which binds to receptors on immune cells called macrophages. These macrophages then switch to an immunosuppressive role, preventing cancer-killing T cells from attacking the tumor.
When researchers blocked this EPO pathway in mice with liver cancer and combined it with anti-PD-1 immunotherapy (similar to the drug Keytruda used in humans), the results were dramatic. While untreated mice lived less than eight weeks, all mice receiving the combined treatment survived for the duration of the 18-week experiment, with complete tumor regression in most cases.
“It’s simple,” Engleman explained. “If you remove this EPO signaling, either by lowering the hormone levels or by blocking the receptors on the macrophages, you don’t just get a reduction in tumor growth, you get tumor regression along with sensitivity to anti-PD-1 treatment.”
The discovery has significant implications for human cancer treatment. Many aggressive cancers, including most liver, pancreas, colon, breast and prostate tumors, show resistance to current immunotherapies precisely because they’re “cold” – lacking sufficient immune cell infiltration.
The Stanford team’s analysis of existing databases confirmed that elevated EPO levels correlate with poorer survival across multiple cancer types, including liver, kidney, breast, colon and skin cancers.
Mechanistically, the researchers found that EPO works through a complex signaling pathway involving a protein called NRF2 (nuclear factor erythroid 2-related factor 2), which drives changes in macrophages that make them immunosuppressive. This newfound understanding provides multiple potential targets for drug development.
Dr. Priscilla N. Kelly, in an accompanying perspective article in Science, noted that the EPO/EPO receptor pathway “may therefore act as a switch to toggle cancer immunity,” highlighting the potential significance of this finding for future treatments.
There are challenges ahead. Non-specifically targeting EPO could cause anemia, though Engleman speculates this might be an acceptable trade-off for effective cancer therapy. An alternative approach being explored is selectively blocking EPO receptors only on macrophages within the tumor environment.
The work represents a paradigm shift in understanding cancer immunology. While cancer researchers have long studied hypoxia (low oxygen conditions) in tumors, no one had connected the dots between hypoxia, EPO production, and immune suppression.
“Hypoxia in tumors has been studied for decades,” Engleman noted. “It just didn’t dawn on anyone, including me, that EPO could be doing anything in this context other than serving as a red blood cell growth factor.”
As Engleman and his team work on designing treatments targeting EPO signaling in human cancers, the discovery offers new hope for difficult-to-treat tumors. For patients with immunotherapy-resistant cancers, this previously overlooked protein could hold the key to turning their bodies’ own immune system against their disease.
“I continue to be amazed by this finding,” Engleman said. “Not every tumor is going to respond in the same way, but I’m very optimistic that this discovery will lead to powerful new cancer therapies.”
The study was funded by the National Institutes of Health. Chiu is a cofounder of ImmunEdge Inc. Engleman is a founder, shareholder and board member of ImmunEdge Inc.
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