Reduced blood flow may prematurely age the bone marrow, weakening the immune system’s ability to fight cancer, according to new research from NYU Langone Health.

The study, published online August 19 in JACC-CardioOncology, found that peripheral ischemia—restricted blood flow in the arteries of the legs—caused breast tumors in mice to grow twice as fast as in mice with normal blood flow. These findings build on a 2020 study by the same team, which showed that ischemia during a heart attack had a similar effect. Ischemia occurs when fatty deposits, such as cholesterol, accumulate in the walls of arteries, leading to inflammation and clotting that restricts the flow of oxygen-rich blood. When this happens in the legs, it results in peripheral arterial disease, a condition affecting millions of Americans and increasing the risk of heart attack or stroke. The study demonstrates that impaired blood flow promotes cancer growth regardless of where the tumor originates in the body. This link between peripheral arterial disease and breast cancer growth highlights the importance of managing metabolic and vascular risk factors as part of a comprehensive cancer treatment strategy. Notably, the research team discovered that restricted blood flow shifts the balance of immune cell populations toward those less capable of fighting infections and cancer, resembling changes seen with aging.

To investigate the mechanisms connecting cardiovascular disease and cancer growth, the researchers developed a mouse model with breast tumors and induced temporary ischemia in one hind limb. The team then compared tumor growth in mice with impaired versus normal blood flow.

Their conclusions are based on the nature of the immune system, which evolved to combat bacteria and viruses as well as to detect and destroy cancer cells. These protective functions depend on reserves of stem cells in the bone marrow, which can be activated as needed to produce key populations of white blood cells throughout life.

Normally, the immune system responds to injury or infection by increasing inflammation to eliminate threats, then reducing it to avoid damaging healthy tissue. This balance is maintained by a mix of immune cells that either activate or suppress inflammation. The researchers found that reduced blood flow disrupts this equilibrium. It reprograms bone marrow stem cells, encouraging the production of “myeloid” immune cells (monocytes, macrophages, neutrophils) that suppress immune responses, while decreasing the production of lymphocytes such as T cells, which help mount a strong anti-tumor response.

The local environment within tumors also showed a similar shift: there was an accumulation of more immunosuppressive cells, including Ly6Chi monocytes, M2-like F4/80+ MHCIIlo macrophages, and regulatory T cells, all of which protect the tumor from immune attack.

Further experiments revealed that these immune changes were long-lasting. Ischemia not only altered the expression of hundreds of genes, pushing immune cells into a more cancer-tolerant state, but also reorganized the structure of chromatin—the protein framework that controls access to DNA—making it harder to activate genes involved in fighting cancer.

The study’s results reveal a direct mechanism by which ischemia promotes cancer growth, reprogramming stem cells in a way similar to aging and fostering immune tolerance. These findings open the door to new strategies for cancer prevention and treatment, such as earlier cancer screening for patients with peripheral arterial disease and the use of anti-inflammatory therapies to counteract these effects.

Looking ahead, the research team hopes to help develop clinical trials to determine whether existing anti-inflammatory therapies can counteract the post-ischemia changes that promote tumor growth.