Cancer treatments: protein identified that blocks the immune system
Current cancer treatments include highly successful drugs, such as monoclonal antibodies targeting so-called ‘immune checkpoints’, for which Tasuku Honjo and James P. Allison were awarded the Nobel Prize in Physiology or Medicine in 2018. These antibodies unlock the immune system by deactivating these biological ‘checkpoints’, which act as molecular brakes on the cell membrane, preventing immune cells from attacking the cancer. However, many patients do not respond to the therapy or develop resistance over time. This limitation is particularly evident in so-called ‘cold tumours’, such as most colorectal and liver cancers.
A new study led by Sapienza University uncovered a previously unknown defence mechanism in tumours. The research, published in the prestigious ‘Journal for ImmunoTherapy of Cancer’, reveals that the TGFBI protein acts as a ‘molecular shield’. This substance was identified through proteomic analysis of factors secreted in the tumour microenvironment (secretome) of patients with liver and colorectal cancer, and was found to be capable of protecting the tumour by inhibiting the immune system.
Researchers discovered that high levels of TGFBI are linked to a shorter life expectancy in cancer patients. This molecule is produced in large quantities both by the tumour itself and by various types of immune cells that infiltrate the tumour. The most significant finding of the research is that, by blocking this protein in the laboratory, T lymphocytes – the cells in our immune system responsible for attacking and destroying the tumour – are reactivated, migrate to the diseased tissues and resume effectively fighting the tumour.
The study therefore opens up new therapeutic avenues: the development of drugs capable of blocking this specific protein could, in fact, provide a new and powerful tool, particularly in cases where traditional treatments using conventional immune checkpoint inhibitors prove ineffective.
Studies are currently underway to confirm similar results across a wide range of checkpoints identified in the tumour secretome, with a view to developing an equally broad spectrum of inhibitors that can help restore the immune system’s defences against a variety of cancers.
The study was carried out with the support of several grants, including those awarded by the AIRC Foundation and the CRUK Hepatocellular Carcinoma Expediter Network (HUNTER) Accelerator Award (VB), and through the multidisciplinary collaboration of various Italian and international centres of excellence, such as the Istituto Superiore di Sanità, Istituto Tumori Regina Elena in Rome, Bambino Gesù Children’s Hospital in Rome, the Cancer Research Centre Lyon (F), University College London (UK).
References: Vincenzo Barnaba et al. Transforming growth factor β induced as a novel secreted immune checkpoint counterinhibiting human tumor-associated T cells (2026). The Journal of ImmunoTherapy of Cancer.
DOI: 10.1136/jitc-2025-012668
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Vincenzo Barnaba