Study Uncovers How Colorectal Cancer Evades Immunotherapy Through Dual Immune Blockade
Barcelona, Spain – A new study from the Institute for Research in Biomedicine (IRB Barcelona) and the National Center for Genomic Analysis (CNAG) has revealed a critical mechanism by wich metastatic colorectal cancer resists immunotherapy. Researchers discovered that the protein TGF-β employs a two-pronged strategy to shield tumors from the immune system, hindering both the arrival of immune cells and their ability to function once inside the tumor. The findings, published in Nature Genetics, offer potential avenues for developing more effective cancer treatments.
The research team, leveraging their expertise in single-cell technologies, cellular immunology, and data analysis, combined experimental models of metastasis in mice with analyses of patient tumor samples. They aimed to understand how TGF-β contributes to immunotherapy resistance, a phenomenon they had previously observed.
The study demonstrates that TGF-β acts as a “no entry” signal,preventing T cells – the immune cells designed to attack cancer – from circulating into the bloodstream and reaching the tumor. Simultaneously, TGF-β alters macrophages, prompting them to produce osteopontin, a protein that further suppresses the proliferation of any T cells that do manage to infiltrate the metastasis. This combined effect renders the tumor largely invisible to the immune system.
“In our experimental models, when we block the action of TGF-β, the immune cells were able to massively enter the tumor and regain their capacity to attack,” explained Dr. Ana Henriques,the paper’s frist author. Dr. Maria Salvany, a co-author, added that combining TGF-β blockade with immunotherapy resulted in “very potent anti-tumor responses.”
While clinical trials for TGF-β inhibitors already exist, their use is currently limited by side effects. The researchers suggest that targeting the mechanisms activated by TGF-β – such as osteopontin production – coudl offer a similar benefit with fewer adverse effects.”In any case, these alternatives will need to be evaluated in clinical trials, and always in combination with immunotherapy,” stated Dr. Eduard Batlle.
Dr. Prados, formerly at IRB Barcelona and now a researcher at the University of Granada, emphasized the broader implications of the research. “Understanding this circuit allows us to search for safer and more selective solutions. The ultimate goal is for immunotherapies, which today only work in a small group of patients, to be able to also benefit the majority of those with metastatic colorectal cancer.”
The project received funding from the Olga Torres Foundation, “la Caixa” Foundation, World Wide Cancer Research, the European Research Council (ERC Advanced Grant), the Spanish Association against Cancer (AECC) through the Excellence Program and other grants for researchers, the Ministry of Science, Innovation and Universities, La Marató de TV3, and the Agency for Management of University and Research Grants (AGAUR).
Journal reference:
Henriques, A., et al. (2025). TGF-β builds a dual immune barrier in colorectal cancer by impairing T cell recruitment and instructing immunosuppressive SPP1+ macrophages. Nature Genetics. doi: 10.1038/s41588-025-02380-2. https://www.nature.com/articles/s41588-025-02380-2
