Hongji Zhang, PhD, (back row, third from left), Allan Tsung, MD, (back row, center) and members of their research team
Metastasis is the leading cause of cancer-related death. For patients with colorectal cancer that spreads to the liver, more than half will experience tumor recurrence even after successful surgery.
A new study from researchers at the University of Virginia School of Medicine reveals that preoperative exercise may significantly reduce this risk. The findings, published in Cell Reports Medicine, uncover how structured exercise before surgery can reprogram the liver’s immune environment to suppress cancer recurrence.
The research team, led by Allan Tsung, MD, and Hongji Zhang, PhD, in UVA’s Department of Surgery, investigated how exercise influences surgical stress, a known trigger of inflammation and immune remodeling that can promote tumor recurrence.
Using a mouse model of surgical stress–induced colorectal cancer liver metastasis, the researchers found that four weeks of moderate treadmill exercise prior to surgery significantly reduced tumor progression. Importantly, exercise did not affect tumor growth in the absence of surgical stress, suggesting that its primary benefit lies in counteracting surgery-induced immune dysfunction.
The team discovered that exercise reshapes the gut microbiome, increasing bacteria that produce butyrate, a beneficial metabolite. Butyrate travels to the liver and reprograms Kupffer cells, the liver’s resident macrophages, shifting them toward an anti-tumor state.
Reprogrammed Kupffer cells produce higher levels of the chemokine CXCL9, which recruits and activates cancer-fighting CD8⁺ T cells and natural killer cells. When Kupffer cells were experimentally depleted, the protective effect of exercise disappeared, confirming their central role in preventing recurrence.
Importantly, the researchers observed similar immune changes in patients with colorectal cancer liver metastases who participated in exercise training prior to surgery, including increased circulating CXCL9 levels and enhanced anti-tumor immune activity.
“These findings provide mechanistic evidence that exercise is not just supportive care, it can actively reshape the immune system in ways that improve cancer outcomes,” the researchers noted.
The study highlights the potential of integrating structured exercise programs into perioperative cancer care. For patients unable to exercise, future therapies targeting the CXCL9-CXCR3 immune pathway may offer similar benefits.
The study was spearheaded by first author Yunwei Zhang, with co-authors Yiyu Zhang, Chengli Shen, Jiye Li, Chunyan Cao, Mohamad El Moheb, and Kaelyn C. Cummins from the Department of Surgery. The multidisciplinary team also included collaborators from institutions across the country, including Han Wang, Ahmad Hamad, Yu Wang, Yujia Xia, Joal Beane, Aslam Ejaz, and Hai Huang. The work opens a promising new avenue for reducing cancer recurrence by harnessing the body’s own immune system through lifestyle intervention.
The research was supported by the NIH, UVA Cancer Center Pilot Study Awards.
Read the article in Cell Reports Medicine.
Filed Under: Research