Scientists have identified a hidden barrier that prevents immunotherapy from working against a rare liver cancer.
Immunotherapy, which activates the body’s own immune system to kill cancer cells, has transformed treatment for some cancers, but it has largely fallen short against a rare, aggressive liver tumor called fibrolamellar carcinoma.
A Cornell University team now reports a possible reason why and points to a familiar, FDA-approved drug that could help remove the roadblock, potentially making immunotherapy far more effective for these patients.
Fibrolamellar carcinoma is unusual in several ways. It tends to strike children and young adults, often in people without underlying liver disease, and it makes up only a small fraction of liver cancers (up to 2%). Because it is rare and can be hard to recognize early, it is frequently discovered after it has spread, leaving patients with limited options.
In a study published in the journal Gastroenterology, researchers found that fibrolamellar tumors can reshape the tissue around them into an immune “no entry” zone. The body may have tumor-fighting T cells ready to go, but the cancer’s local environment keeps those cells penned in at the edges, away from the tumor cells they are supposed to kill. This immune bottleneck is known as T-cell exclusion, and it offers a clear explanation for why immune checkpoint inhibition has not delivered the kind of results seen in other cancers.
Why Immunotherapy Often
“Our results provide among the first indications of why a type of immunotherapy called immune checkpoint inhibition hasn’t worked well in these patients, and even if this particular drug isn’t the end-all-be-all, it teaches us that this T-cell exclusion phFailsenomenon is an important one to tackle in fibrolamellar carcinoma,” said Praveen Sethupathy, professor of physiological genomics and the paper’s co-senior author.
Immune checkpoint inhibitors are designed to stimulate the body’s T cells so they can move into the center of a tumor and destroy cancer cells. These drugs have been highly effective in treating several cancers, including those of the liver, lung, kidney, and bladder, as well as melanoma.
Still, other cancers, such as pancreatic, prostate, and brain tumors, often do not respond. The structure of the tumor microenvironment and the trapping of T cells help explain why some cancers resist this type of therapy.
Testing a Potential Combination Therapy
To explore whether AMD3100 could overcome this barrier, researchers tested the drug on slices of tumors obtained from patients. They found that AMD3100 enabled T cells to enter the tumor core. When paired with immune checkpoint inhibitors, the drug further boosted T cell activity and led to a marked increase in tumor cell death.
Sethupathy and colleagues are currently searching for liver cancer clinicians who might be interested in starting clinical trials for the new treatment. “A compelling feature of this work is that AMD3100 is already FDA-approved, which can reduce risks and potentially speed up timelines for clinical trials in fibrolamellar carcinoma,” Sethupathy said.
Reference: “Overcoming CXCR4-Mediated T-Cell Exclusion Potentiates Antitumor Cytotoxicity in Fibrolamellar Carcinoma” by Jason A. Carter, Lindsay K. Dickerson, Andreas Stephanou, Sheela R. Damle, Kristin E. Goodsell, Sara K. Daniel, Kevin M. Sullivan, Bo Shui, Xiuyun Jiang, Heidi L. Kenerson, Renske J.E. van den Bijgaart, Alaa R. Farghli, Yongjun Liu, Emily Beirne, Kevin P. Labadie, Jack Cernak, Sardar Shahmir B. Chauhan, Jose Mario Bello Pineda, Annalyssa N. Long, Anna E. Elz and Venu G. Pillarisetty, 17 February 2026, Gastroenterology.
DOI: 10.1053/j.gastro.2025.10.006
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