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Colorectal cancer is one of the leading causes of cancer death worldwide. In recent years, immunotherapies—treatments that reactivate the immune system to attack tumor 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 tumors 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 tumor from the blood. On the other hand, it blocks the expansion of the few T cells that manage to infiltrate the tumor.

“Our work shows that tumors defend themselves against immunotherapies by manipulating their environment to slow the immune response on two fronts. Understanding this communication language between the tumor and the immune system opens the door to designing strategies that can deactivate these defenses 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 tumor microenvironment, we have been able to characterize 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.

Inhibition of T cell motility by PD-1–PD-L1 interactions but not by TGF-β signaling. Credit: Nature Genetics (2025). DOI: 10.1038/s41588-025-02380-2

Two barriers that block defenses

The study combines experimental models of metastasis in mice with analyses of tumors 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 tumor 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 tumor virtually invisible to the immune system.

“In our experimental models, when we blocked the action of TGF-β, the immune cells were able to massively enter the tumor 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-tumor 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, is 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.

More information: Ana Henriques et al, TGF-β builds a dual immune barrier in colorectal cancer by impairing T cell recruitment and instructing immunosuppressive SPP1+ macrophages, Nature Genetics (2025). DOI: 10.1038/s41588-025-02380-2.

Citation: How colorectal cancer evades immunotherapy using a dual barrier (2025, November 7) retrieved 7 November 2025 from https://medicalxpress.com/news/2025-11-colorectal-cancer-evades-immunotherapy-dual.html

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