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).
USF Media Contact:
John Dudley
Assistant director
National media relations
(814) 490-3290 (cell)
jjdudley@usf.edu
TGH Media Contact:
Beth Hardy, APR
Assistant Manager
Publications & Physician Communications
(727) 510-6363 (cell)
ehardy@tgh.org
Megha Kalra
Public Relations & Communications Division
Office of Public Relations and Social Collaboration
Hokkaido University
Email: en-press@general.hokudai.ac.jp
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About the University of South Florida
The University of South Florida is a top-ranked research university serving approximately 50,000 students from across the globe at campuses in Tampa, St. Petersburg and USF Health. In 2026, U.S. News & World Report recognized USF as a top 50 public university for the eighth consecutive year. U.S. News also ranks the USF Health Morsani College of Medicine in the highest tier, placing it as one of the top 16 medical schools in the nation. USF is a member of the Association of American Universities (AAU), a group that includes only the top 3% of universities in the U.S. With an all-time high of $750 million in research funding in 2025 and as a top 20 public university for producing U.S. patents, USF uses innovation to transform lives and shape a better future. The university generates an annual economic impact of nearly $10 billion for the state of Florida. USF’s Division I athletics teams compete in the American Conference. Learn more at www.usf.edu .
About Tampa General Hospital
Tampa General Hospital, Florida’s premier academic health system, is a 1,530-bed not-for-profit network of hospital and outpatient services spanning Florida. As the only center for Level l trauma and comprehensive burn care center serving 23 counties, Tampa General delivers world-class care. The system’s hospitals include Tampa General Hospital, Tampa General Rehabilitation Hospital, Tampa General Behavioral Health Hospital, all in Tampa; Tampa General Brooksville, Tampa General Spring Hill and Tampa General Crystal River. Tampa General is the highest-ranked hospital in Tampa Bay in U.S. News & World Report's 2026-2027 Best Hospitals for 11 consecutive years, with five medical specialties ranking among the top 50, two additional medical specialties ranked among the top 100 best hospital programs and two specialties ranked in the top 10% in the United States. As the first hospital in Florida to open a clinical command center for real-time situational awareness, the academic health system has elevated its digital care coordination center to the next level by leveraging artificial intelligence (AI) and its analytics platform across inpatient and outpatient care to ensure patients receive leading-edge care as quickly and safely as possible. Tampa General’s commitment to growing and developing its team members is recognized by four prestigious Forbes magazine rankings — in the 2026 America's Best Large Employers ranked as the Tampa Bay region's #1 employer in the healthcare category for the sixth year in a row, the 2026 America's Best Employers for Company Culture , in the top 100 for the 2026 America's Best Employers for New Grads and the 2026 America's Best Employers for Women .
Tampa General is the area’s safety-net hospital, caring for anyone regardless of ability to pay; in fiscal year 2024, Tampa General provided a net community benefit of approximately $289.1 million in the form of healthcare for underinsured patients, community education and financial support to community health organizations in Tampa Bay. It is recognized as one of the leading adult solid organ transplant centers in the nation and is the primary teaching hospital for the USF Health Morsani College of Medicine. With five medical helicopters, Tampa General transports critically injured or ill patients from surrounding counties to receive the advanced care their conditions require. Tampa General has a nationally accredited comprehensive stroke center and its 32-bed Neuroscience Intensive Care Unit is the largest on the West Coast of Florida. It is home to the Muma Children’s Hospital at TGH, the Jennifer Leigh Muma 82-bed neonatal intensive care unit and a nationally accredited rehabilitation center. Tampa General’s footprint includes TGH North, which consists of three hospitals and several outpatient locations in Citrus and Hernando counties; Tampa General Medical Group Primary Care offices; TGH Family Care Center Kennedy; TGH outpatient centers; TGH Virtual Health; and TGH Imaging outpatient radiology centers throughout Hillsborough, Pasco, Pinellas and Palm Beach counties. Tampa Bay area residents receive world-class care from the TGH Urgent Care, powered by the Fast Track network of clinics. To see a medical care professional live anytime, anywhere on a smartphone, tablet or computer, visit Virtual Health | Tampa General Hospital (tgh.org) . For more information, go to www.tgh.org .
About Hokkaido University
Founded in 1876 as Sapporo Agricultural College, Hokkaido University is one of the oldest, largest, and most prestigious universities in Japan. The university attracts prospective students from all around the globe with the diverse degree programs offered and the year-round scenic beauty. The campuses are located in the cities of Sapporo and Hakodate in Hokkaido, and 21 facilities are spread throughout Hokkaido and mainland Japan.
Journal of Experimental & Clinical Cancer Research
Data/statistical analysis
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