Immunotherapy has revolutionized cancer treatment in recent years, leveraging the body’s own immune system to identify and destroy malignant cells. However, its success has been uneven across different cancer types. A particularly challenging malignancy is fibrolamellar carcinoma (FLC), a rare and deadly liver cancer that predominantly affects children and young adults. Despite the promise shown by immune checkpoint inhibitors in many cancers, they have so far failed to deliver meaningful results for FLC patients. Now, groundbreaking research from Cornell University provides new mechanistic insights into why immunotherapy falters in FLC and offers hope through repurposing an FDA-approved drug that could unlock the immune system’s potential against these tumors.
Fibrolamellar carcinoma represents a small fraction of liver cancers—approximately 2%—yet its impact on the affected population is devastating due to its aggressive nature and lack of effective treatments. Frequently diagnosed at advanced stages where metastasis has already occurred, FLC patients face limited options and poor prognoses. Current therapeutic modalities have been insufficient, urging researchers to explore novel strategies, including immunotherapy, which has transformed outcomes in several other liver and solid tumors.
The newly published study in the journal Gastroenterology reveals a previously underappreciated mechanism termed “T-cell exclusion,” whereby fibrolamellar tumors reprogram their local microenvironment to spatially segregate cytotoxic T cells away from tumor cells. This immunological barrier effectively neutralizes the T cells’ anti-cancer functions despite their activation, explaining the resistance to immune checkpoint blockade therapies. By dissecting the tumor microenvironment using cutting-edge patient-derived tumor slice models, the researchers provided compelling evidence that this physical and biochemical sequestration prevents effective immune surveillance and tumor cell killing in FLC.
At the heart of the study is the investigation of AMD3100, also known as plerixafor, a drug originally approved by the FDA for hematopoietic stem cell mobilization in patients with lymphoma and multiple myeloma. Researchers discovered that AMD3100 can interfere with the molecular signals responsible for T-cell sequestration within fibrolamellar tumors. Specifically, AMD3100 antagonizes the CXCR4 receptor, a chemokine receptor implicated in the retention and localization of immune cells in various tissues. By blocking CXCR4, the drug dismantles the tumor’s immunosuppressive niche, enabling T cells to infiltrate the tumor core where they can mount an anti-tumor response.
Further experiments combining AMD3100 with immune checkpoint inhibitors demonstrated a synergistic effect. The mobilization of T cells into the tumor intensified their cytotoxic activity when paired with checkpoint blockade, leading to significantly increased tumor cell death in ex vivo assays. This finding highlights the potential of combining agents that modify the tumor microenvironment with immunotherapies to overcome resistance mechanisms that have stymied progress in treating FLC and possibly other refractory tumors.
Professor Praveen Sethupathy, who co-led the study, emphasized the clinical implications, noting that while AMD3100 alone may not be the definitive solution, the identification of T-cell exclusion as a critical barrier opens new avenues for therapeutic intervention. The repurposing of an already FDA-approved drug substantially reduces the hurdles associated with drug development, potentially accelerating the translation of these findings into clinical trials and, ultimately, patient care.
The significance of this research extends beyond fibrolamellar carcinoma. T-cell exclusion is increasingly recognized as a common obstacle in various “cold” tumors—cancers that fail to elicit robust immune responses. By unraveling how the tumor microenvironment modulates immune cell localization and function, the study contributes to a broader understanding of tumor immunobiology and will likely inform future cancer immunotherapy strategies.
Historically, immune checkpoint inhibitors such as PD-1/PD-L1 and CTLA-4 blockers have been heralded for their effectiveness in treating melanoma, non-small cell lung cancer, and several other malignancies. Their mechanism involves releasing the so-called “brakes” on the immune system, allowing T cells to become fully activated and attack cancer cells. However, in tumors characterized by a hostile microenvironment or immune exclusion, the presence of activated T cells in the bloodstream or lymphoid organs is insufficient if they cannot physically access the tumor cells.
The Cornell team’s use of patient-derived tumor slices represents a cutting-edge approach to modeling the tumor microenvironment ex vivo while maintaining the spatial and cellular complexity inherent to native tumors. Such models enable precise evaluation of drug effects on immune cells and tumor interactions in a more physiologically relevant context than traditional cell culture systems.
As a next step, the researchers are actively seeking collaborations with clinicians specializing in liver cancers to initiate clinical trials assessing the efficacy and safety of AMD3100 in combination with immune checkpoint inhibitors for patients with fibrolamellar carcinoma. The potential to repurpose an existing drug could shorten the timeline to approval and provide a treatment option for a devastating disease that currently lacks effective therapies.
This breakthrough exemplifies the power of interdisciplinary research combining immunology, cancer biology, and clinical medicine. It underscores the need for continued exploration of tumor microenvironment dynamics and innovation in immunotherapy to achieve durable responses across a broader spectrum of cancers.
Fibrolamellar carcinoma’s unique biology has posed significant challenges to the oncology community, but through innovative study designs and strategic drug repurposing, hope is emerging for patients with this rare and aggressive liver tumor. As these findings prompt new clinical investigations, they also pave the way for better understanding and overcoming immune resistance mechanisms in other malignancies.
In conclusion, the Cornell study marks a pivotal advance in cancer immunotherapy by not only explaining the failure of checkpoint inhibitors in fibrolamellar carcinoma but also proposing a tangible solution through AMD3100. This work highlights a paradigm shift in approaching immune resistance: modifying the tumor microenvironment to enable immune cell infiltration is as critical as activating immune cells themselves. The prospect of combining FDA-approved agents to unlock the immune system’s full potential heralds a new chapter for treating rare and refractory cancers.
Subject of Research: Immunotherapy resistance and tumor microenvironment modulation in fibrolamellar carcinoma
Article Title: Disrupting T-cell Exclusion in Fibrolamellar Carcinoma to Enhance Immunotherapy Efficacy
News Publication Date: February 17, 2026
Web References: https://www.sciencedirect.com/science/article/pii/S0016508525061219?dgcid=coauthor, http://dx.doi.org/10.1053/j.gastro.2025.10.006
References: Study published in Gastroenterology, DOI: 10.1053/j.gastro.2025.10.006
Keywords: Immunology, Immune disorders, Immune response, Immune system, Cancer immunology, Fibrolamellar carcinoma, Tumor microenvironment, T-cell exclusion, Immune checkpoint inhibition, AMD3100, CXCR4 antagonism, Cancer immunotherapy
