Barcelona, 7 November 2025 – Colorectal cancer remains a leading cause of cancer-related deaths globally. Despite the transformative impact of immunotherapies on various cancer treatments, the majority of patients with metastatic colorectal cancer fail to respond effectively. A groundbreaking study led by Drs. Eduard Batlle and Alejandro Prados from IRB Barcelona, in collaboration with Dr. Holger Heyn from CNAG, uncovers the mechanisms hindering these treatments, offering new hope for improved strategies.
Published in the prestigious journal Nature Genetics, the study reveals that a hormone called TGF-β enables colorectal tumors to construct a dual barrier, effectively neutralizing the immune system’s attack. This barrier operates on two fronts: it prevents T lymphocytes from reaching the tumor and stifles the proliferation of any T cells that infiltrate the tumor.
Understanding the Dual Barrier
The research, combining experimental models in mice and patient tumor analyses, sheds light on how TGF-β acts as a formidable “no entry” signal. It not only restricts T cells from circulating in the bloodstream but also alters macrophages to produce osteopontin, a protein that further impedes T cell multiplication within the tumor.
“Our work demonstrates that tumors manipulate their environment to slow the immune response on two fronts,” explains Dr. Eduard Batlle, ICREA research professor and head of the Colorectal Cancer Laboratory at IRB Barcelona. “Understanding this communication between the tumor and the immune system opens the door to strategies that can deactivate these defenses and enhance immunotherapy efficacy.”
Single-Cell Genomics: A Key to Unlocking Barriers
Dr. Holger Heyn, leading the Single Cell Genomics Group at CNAG, highlights the role of cutting-edge technology in this discovery. “By sequencing individual cells within the tumor microenvironment, we characterized the main players affected by TGF-β. This approach allowed us to identify new therapeutic targets to improve colorectal cancer treatments,” he notes.
“Applying state-of-the-art technology, we observed how TGF-β blocks immunotherapy efficacy and identified new therapeutic targets to improve colorectal cancer treatments.” – Dr. Holger Heyn
Potential for New Therapeutic Strategies
While clinical trials for TGF-β inhibitors are underway, their use is limited due to significant side effects. The study suggests alternative strategies, such as blocking TGF-β activated mechanisms, including osteopontin production, could achieve similar results with fewer risks.
“In our experimental models, blocking TGF-β allowed immune cells to enter the tumor en masse and regain their attack capacity,” explains Dr. Ana Henriques, the study’s first author. Dr. Maria Salvany adds, “Combining this blockade with immunotherapy led to potent anti-tumor responses.”
Future Directions and Clinical Implications
According to Dr. Eduard Batlle, these alternatives require evaluation in clinical trials, ideally in combination with existing immunotherapies. “Understanding this circuit allows us to search for safer and more selective solutions,” he emphasizes. The ultimate goal is to extend the benefits of immunotherapies to a broader patient group, especially those with metastatic colorectal cancer.
“The ultimate goal for immunotherapies, which today only work in a small group of patients, is to benefit the majority of those with metastatic colorectal cancer.” – Dr. Alejandro Prados
Collaborative Efforts and Funding
The study was conducted by the Institute for Research in Biomedicine (IRB Barcelona) and the National Center for Genomic Analysis (CNAG), with financial support from various organizations, including the Olga Torres Foundation, “la Caixa” Foundation, World Wide Cancer Research, and the European Research Council, among others.
This development represents a significant step forward in the fight against colorectal cancer, offering new avenues for treatment and hope for patients worldwide. As researchers continue to explore these findings, the potential for more effective and less toxic cancer therapies grows ever closer.
