In a recent study funded by FCF, researchers at the University of Washington, Fred Hutchinson Cancer Center, and Cornell University shed important light on why immunotherapy has struggled to work in fibrolamellar carcinoma (FLC). Led by Dr. Venu G. Pillarisetty and Dr. Praveen Sethupathy, a collaborative, multidisciplinary team set out to understand why treatments like PD‑1 checkpoint inhibitors often fail in FLC, even though the cancer has a genetic driver that should make it visible to the immune system. The resulting paper, Overcoming CXCR4-Mediated T-Cell Exclusion Potentiates Antitumor Cytotoxicity in Fibrolamellar Carcinoma, was included in the April edition of the journal Gastroenterology.

By closely studying real human FLC tumors, the researchers discovered that immune cells called T cells are present—but they are blocked from reaching the cancer cells they need to attack.

The study shows that FLC protects itself in two ways: first, by physically trapping T cells in the tumor’s dense fibrous tissue using a chemical signal (the CXCL12/CXCR4 pathway), and second, by shutting down the few T cells that do reach the tumor through immune “brakes” like PD‑1. The researchers demonstrated that blocking only one of these barriers is not enough to drive cancer cell death. Instead, combining a drug that mobilizes T cells with a drug that reactivates the T cells leads to much stronger cancer cell killing. Together, these findings provide the clearest explanation to date for immune resistance in FLC and offer an approach for designing smarter, combination immunotherapy trials for this rare and devastating cancer.

Additional details and the full publication can be read here.