TAMPA, Fla. (Oct. 14, 2026) – Researchers at the University of South Florida , Tampa General Hospital and Hokkaido University have uncovered an important mechanism behind immune evasion in metastatic colorectal cancer (mCRC). The finding challenges a 30-year-old theory in cancer research and identifies a molecular pathway that offers a new target for treatment.
The international study, newly published in the Journal of Experimental & Clinical Cancer Research , found that a biological process long thought to occur primarily inside cancer cells instead appears to play a central role in the environment outside metastatic tumors, where it is associated with immune suppression, more advanced disease and poorer patient survival.
In laboratory experiments, researchers blocked two key components of the pathway, allowing healthy killer T cells to return and successfully attack the cancer cells again. The findings could explain why most metastatic colorectal cancers respond poorly to certain immunotherapies and point toward strategies for making those treatments more effective.
"For decades, we have thought of this pathway largely in terms of what happens inside the cancer cell and whether the cell survives or dies," said senior author Timothy J. Yeatman, MD, Professor of Surgery at the USF Health Morsani College of Medicine and associate center director for Translational Research and Innovation at the TGH Cancer Institute . "What we found suggests that much of the important activity is actually happening in the neighbourhood around the tumour — the tumour microenvironment (TME) — where it creates an environment that prevents the immune system from effectively attacking the cancer."
About 30 years ago, the "rheostat" model proposed that elevated sphingosine-1-phosphate (S1P) promotes tumor cell growth, whereas higher ceramide levels trigger cell death. Under this traditional model, scientists thought that cancer cells used this internal mechanism to control their own fate, turning up S1P to grow uncontrollably or turning down ceramide to avoid dying, just like a physical rheostat, or dimmer switch, controls electrical current by increasing or decreasing resistance.
The new, multi-institute study showed that an important part of that balancing act occurs outside the cancer cells themselves in immune cells called macrophages.
By examining 574 human colon cancer tissue samples through advanced mapping technology, the team found that as colorectal cancer spreads, levels of pro-cancer growth lipids (S1P) increased, whereas levels of the cancer cell-killing lipid (ceramide) dropped significantly.
The previous theory assumed this chemical balancing act was happening inside the tumor cells. But advanced spatial mapping showed that the molecules that make and receive signals to "stay alive" are concentrated in the surrounding healthy-looking support tissue and specialized immune cells. This creates a state of ongoing, unhealthy inflammation that blocks killer immune cells, preventing them from getting close enough to fight and destroy the tumor.
The researchers also identified a specific three-gene signature that acts as a warning of aggressive cancer. High activity of this gene signature is strongly linked to late-stage cancer, tumors spreading into lymph nodes, lower patient survival rates and poor responses to standard immunotherapy drugs. The lab experiments support further investigation into whether targeting the pathway could alter the immune environment surrounding a tumor and help immune cells function more effectively.
"Metastatic colorectal cancer remains notoriously resistant to checkpoint inhibitors. Our findings show that elevated S1P and its receptor S1PR3 act as a localized biochemical shield, driving out cytotoxic T cells and creating an immunosuppressive microenvironment," the authors wrote in the study, said Associate Professor Siddabasave Gowda B. Gowda at the Graduate School of Global Food Resources and Faculty of Health Sciences, Hokkaido University.
"Targeting this pathway offers a therapeutic strategy to break these barriers, restore immune cell infiltration and potentially make immunotherapies effective for patients with advanced disease."
Colorectal cancer is the second-leading cause of cancer-related mortality worldwide, with five-year survival rates dropping to just 14% once it spreads to other parts of the body. Although immune therapies have revolutionized treatment for several cancers, most colorectal tumors at this stage are resistant to these treatments. Understanding why is a major clinical challenge.
These findings highlight S1P/S1PR3 pathway inhibition as a promising combination strategy to boost immunotherapy efficacy in colorectal cancer.
Funding: The study was supported by Tampa General Hospital Foundation, NCI (U01CA293474, R35CA197570, P50CA236733), and the Japan Society for the Promotion of Science (JSPS) KAKENHI (25K00258).
