A new study conducted by the Institute for Research in Biomedicine (IRB Barcelona) and the National Centre for Genomic Analysis (CNAG), both located at the Barcelona Science Park, reveals how metastatic colorectal tumours block the immune system through two complementary mechanisms. The research, published in Nature Genetics, identifies osteopontin as a key protein responsible for hindering the action of defensive cells within the tumour. These results open new avenues for designing combination therapies that could make immunotherapy effective in more patients.

Colorectal cancer is one of the leading causes of cancer-related death worldwide. In recent years, immunotherapies — treatments that reactivate the immune system to attack tumour cells — have transformed the treatment of many types of cancer. However, most patients with metastatic colorectal cancer do not respond to these therapies. Now, the study led by Dr. Eduard Batlle and Dr. Alejandro Prados from IRB Barcelona, together with Dr. Holger Heyn from CNAG, reveals the mechanisms involved that limit the effectiveness of these treatments and suggests new strategies that could improve their efficacy in patients with metastatic colorectal cancer.

The researchers observed that the hormone TGF-β causes colorectal tumours to create a double barrier that prevents immune system cells from attacking the disease. On one hand, TGF-β prevents T lymphocytes — the cells responsible for eliminating cancer cells — from reaching the tumour from the bloodstream. On the other hand, it also blocks the expansion of the few T cells that manage to infiltrate the tumour.

“Our work shows that tumours defend themselves against immunological therapies by manipulating their environment to suppress the immune response on two fronts. Understanding this language of communication between the tumour and the immune system opens the door to designing strategies that can deactivate these defences and thus improve the effectiveness of immunotherapy,” explains Dr. Eduard Batlle, ICREA researcher, head of the Colorectal Cancer Laboratory at IRB Barcelona, and CIBERONC investigator.

“By sequencing individual cells within the tumour microenvironment, we were able to characterize the main players affected by TGF-β,” explains Dr. Holger Heyn, leader of the Single Cell Genomics Group at CNAG and ICREA researcher. “By applying cutting-edge technology, we observed how TGF-β blocks the effectiveness of immunotherapy and identified new therapeutic targets to improve treatments against colorectal cancer.” The expertise of the CNAG team in single-cell technologies, cellular immunology, and data analysis was key to uncovering how TGF-β blocks the immune system in metastatic colorectal cancer.

Two walls that block the defences

The study combines experimental models of metastasis in mice with analyses of tumours from patients. The researchers sought to understand how TGF-β mediates resistance to immunotherapy, a phenomenon they had previously observed.

What they have observed in this study is that TGF-β acts as a “no entry” signal: it prevents T cells capable of attacking the tumour from circulating in the blood. Simultaneously, it modifies cells called macrophages to produce a protein, osteopontin, which in turn slows the multiplication of the few T cells that manage to infiltrate the metastasis. The combination of both actions makes the tumour virtually 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 tumour and regain their capacity to attack,” explains Dr. Ana Henriques, the paper’s first author. “Furthermore, when combining this blockade with immunotherapy, we observed very potent anti-tumour responses,” adds Dr. Maria Salvany, also co-author.

New therapeutic strategies

Although clinical trials for TGF-β inhibitors exist, the use of these medications in patients is currently limited due to their side effects. This study suggests that alternative strategies, such as blocking the mechanisms activated by TGF-β—including the production of osteopontin—could achieve a similar effect. “In any case, these alternatives will need to be evaluated in clinical trials, and always in combination with immunotherapy,” comments Dr. Eduard Batlle.

“Understanding this circuit allows us to search for safer and more selective solutions. The ultimate goal 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,” concludes Dr. Prados, formerly at IRB Barcelona and now a researcher at the University of Granada.

» Article de referència: A dual TGF-β immunosuppressive barrier impedes T cell recruitment and expansion in metastatic colorectal cancer. Ana Henriques*, Maria Salvany-Celades*, Paula Nieto, Sergio Palomo-Ponce, Marta Sevillano, Xavier Hernando-Momblona, Emily Middendorp-Guerra, Montserrat Llanses, Elisabeth Marjolein Haak, Juan Nieto, Ginevra Caratú, Domenica Marchese, Sara Ruiz, Sebastien Tosi, Theresa Suckert, Jordi Badia-Ramentol, Adrià Caballé-Mestres, Carolina Sánchez, Lidia Mateo, Daniele V. F. Tauriello, Antoni Riera, Elena Sancho, Camille Stephan-Otto Attolini, Alejandro Pradosº, Holger Heynº & Eduard Batlleº. Nature Genetics (2024) doi: 10.1038/s41588-025-02380-2.

» Link to the news: IRB Barcelona website [+]