Study Uncovers How Colorectalโค Cancer Evades Immunotherapy Through Dual Immune Blockade
Barcelona, Spain – A new study from the Institute for โขResearch in Biomedicine (IRBโข Barcelona) and โคthe National Center for Genomic Analysis (CNAG) has โrevealed a critical mechanism by wich metastatic colorectal โcancer resists immunotherapy. Researchers discovered that the protein TGF-ฮฒ employs a two-pronged strategy to shield tumors from the immune system, hindering both the arrivalโข of immune cells and their ability to function once inside the tumor. The findings, publishedโข in Nature Genetics, offer potential avenues โฃfor developing more effective cancer treatments.
Theโฃ research team, leveraging their expertise in single-cell technologies, cellular immunology, and data analysis, combined experimental models of metastasis in mice with analyses ofโค patient tumor samples. They aimed to understand how TGF-ฮฒ contributes to immunotherapy resistance, a phenomenon they had previously observed.
The โstudy demonstrates that โTGF-ฮฒ acts as a “no entry” signal,preventing T cells – โthe immune cells designed to attack cancer – from circulating into the bloodstream and reaching the tumor. Simultaneously, TGF-ฮฒ alters macrophages, prompting them to produce osteopontin, a protein that furtherโ suppresses the proliferation of โany T โฃcells that do manage to โคinfiltrate the metastasis. This combined effect โขrenders the tumor largely invisible to the immune system.
“In our experimental models, when we block the action of TGF-ฮฒ, the โฃimmune 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-ฮฒ blockade with immunotherapy resulted in “very potent anti-tumor responses.”
While clinical trials for TGF-ฮฒ inhibitors already exist, their use โis currently limited by side effects. The researchers suggest that targeting the mechanisms activated by TGF-ฮฒ – such โas 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 alwaysโ in combination with immunotherapy,” stated Dr. Eduard Batlle.
Dr. Prados, formerly โat IRB Barcelona and now a researcher at theโ University of Granada, emphasized the broader implications of the research. “Understanding this circuit allows us to search for safer and more selective solutions. The โultimate goal is for immunotherapies, which today โคonly work in a small โgroup of patients, to be able to also benefit the โmajority of those with metastatic colorectal cancer.”
The project received funding from โthe Olga Torres Foundation, “laโ Caixa” Foundation, World Wide Cancer Research, the European Research Council (ERC Advanced Grant), the Spanish Associationโ against Cancer (AECC) through the Excellence Program and other grants for researchers, the Ministry of Science, Innovation โand Universities,โ La Maratรณ de TV3, and the Agency for Management of University and Research Grants (AGAUR).
Journal โreference:
Henriques, A., et al. (2025). TGF-ฮฒ builds a dual immune barrier in colorectal cancer โฃby impairing T cell recruitment and instructingโ immunosuppressive SPP1+ macrophages. โ Nature Genetics. doi: 10.1038/s41588-025-02380-2. https://www.nature.com/articles/s41588-025-02380-2
