Colorectal cancer evades immunotherapy using a dual barrier

Colorectal cancer is one of the leading causes of cancer 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 treatments.

A study led by Drs. Eduard Batlle and Alejandro Prados (both from IRB Barcelona and members of CIBERONC), together with Dr. Holger Heyn, from CNAG, sheds light on the mechanisms that limit the efficacy of these treatments and suggests strategies to improve it. Published in Nature Genetics, the study reveals how, via a hormone called TGF-β, colorectal tumours build a dual barrier that prevents cells from the immune system from acting against the cancer. On the one hand, TGF-β prevents a sufficient number of T lymphocytes (the cells responsible for eliminating cancer cells) from reaching the tumour from the blood. On the other hand, it blocks the expansion of the few T cells that manage to infiltrate the tumour.

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

“By sequencing individual cells within the tumour microenvironment, we have been able to characterise the main players affected by TGF-β,” explains Dr. Holger Heyn, Single Cell Genomics Group Leader at CNAG and ICREA Research Professor. “Applying state-of-the-art technology, we observed how TGF-β blocks immunotherapy efficacy and identified new therapeutic targets to improve colorectal cancer treatments.” The CNAG team’s expertise 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 barriers that block 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.

The study was performed by the Institute for Research in Biomedicine (IRB Barcelona) and the National Center for Genomic Analysis (CNAG). 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 Programme 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).

Related article:
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 Sanchez, 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