{"id":22476,"date":"2026-11-04T13:23:39","date_gmt":"2026-11-04T12:23:39","guid":{"rendered":"https:\/\/www.areasciencepark.it\/cancro-al-seno-il-tessuto-rigido-lo-rende-invisibile-al-sistema-immunitario\/"},"modified":"2026-11-06T10:23:57","modified_gmt":"2026-11-06T09:23:57","slug":"breast-cancer-how-tissue-rigidity-makes-cancer-invisible-to-the-immune-system","status":"publish","type":"post","link":"https:\/\/www.areasciencepark.it\/en\/breast-cancer-how-tissue-rigidity-makes-cancer-invisible-to-the-immune-system\/","title":{"rendered":"Breast cancer: how tissue rigidity makes cancer invisible to the immune system"},"content":{"rendered":"<p class=\"wp-block-paragraph\">Findings published in <em>Cancer Discovery<\/em>, a journal of the American Association for Cancer Research, from a study led by Giannino Del Sal of the ICGEB,\u00a0University of Trieste, and the \u201cFondazione Istituto di Oncologia Molecolare\u201d (IFOM), and supported by the AIRC Foundation for Cancer Research.reveal that the Pin1 protein links tumour tissue stiffness to the ability to evade immune defences. In laboratory experiments, inhibiting Pin1 with already approved drugs made \u201ccold\u201d tumours responsive to immunotherapy.<\/p>\n<p class=\"wp-block-paragraph\">Trieste, 29 October 2026 \u2013 The stiffness of the tissues surrounding tumour cells can help those cells evade immune surveillance. Findings from a recent study coordinated by Giannino Del Sal of the University of Trieste, ICGEB and the Fondazione Istituto di Oncologia Molecolare (IFOM) have revealed a possible mechanism behind this process. Tissue stiffness promotes the accumulation of Pin1 in the nucleus, where it keeps DNA sequences capable of stimulating an immune response silenced.<\/p>\n<p class=\"wp-block-paragraph\">The study, published in the journal Cancer Discovery, involved researchers from IFOM and Italian and international centres. It was made possible by long-term support from the AIRC Foundation for Cancer Research through the AIRC \u201c5 per mille\u201d programme\u00a0Metastasis as Mechanodisease, coordinated by Professor Stefano Piccolo of the University of Padua and IFOM in Milan.<\/p>\n<p class=\"wp-block-paragraph\"><strong>Stiff and \u201ccold\u201d tumours<\/strong><\/p>\n<p class=\"wp-block-paragraph\">In many tumours, the extracellular matrix \u2013 the scaffold that supports cells \u2013 becomes rich in collagen and particularly stiff. This condition is often associated with so-called immunologically \u201ccold\u201d tumours, in which immune cells are scarce or insufficiently active and therefore unable to recognise and eliminate tumour cells. These features may contribute to the poor response of such tumours to immune checkpoint inhibitors, drugs that release the brakes on the immune response against cancer.<\/p>\n<p class=\"wp-block-paragraph\">Researchers found that stiffness promotes the accumulation of Pin1 in the nuclei of tumour cells. There, the protein helps keep chromatin \u2013 the structure in which DNA is organised \u2013 compact and regulates the expression of transposable elements: repetitive DNA sequences in the genome that can move and whose reactivation can generate signals recognised by the immune system.<\/p>\n<p class=\"wp-block-paragraph\">The resulting DNA accumulates in the cytoplasm and activates an alarm system, the cGAS-STING pathway, which alerts the immune system. These elements also generate new targets, known as neoantigens, that lymphocytes can recognise. The tumour therefore changes from \u201ccold\u201d to \u201chot\u201d.<\/p>\n<p class=\"wp-block-paragraph\">Targeting Pin1 to make the tumour more visible Using experiments in cultured human cells and preclinical models, together with analyses of patient samples and clinical data, the team showed that the loss or inhibition of Pin1 reactivates certain transposable elements, including LINE1.<\/p>\n<p class=\"wp-block-paragraph\">This has two effects. First, DNA accumulates in the cytoplasm, outside the nucleus, activating the cGAS-STING cellular surveillance system. This sensor detects DNA in an abnormal location and stimulates the production of type I interferons, molecules that help mobilise immune defences. Tumours can adopt several strategies to prevent cGAS-STING activation and thereby evade immune surveillance. The study identified Pin1-mediated suppression of transposable element expression as one of these crucial escape mechanisms. Second, reactivation of transposable elements promotes the production of new peptides, small protein fragments that T cells can recognise as foreign. Targeting Pin1 therefore acts on two fronts: it activates signals that recruit immune defences and makes tumour cells more recognisable. In the experimental systems studied, these effects were accompanied by greater lymphocyte infiltration into the tumour and a reduction in components that suppress the immune response.<\/p>\n<p class=\"wp-block-paragraph\"><strong>Already available drugs improve the response to immunotherapy<\/strong><\/p>\n<p class=\"wp-block-paragraph\">In preclinical experimental models of breast cancer resistant to immunotherapy, the loss of Pin1 improved the response to immunotherapies that release one of the brakes on T-cell activity. The researchers then evaluated all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), two drugs that can inhibit Pin1 activity and are already used in clinical practice to treat acute promyelocytic leukaemia, a subtype of acute myeloid leukaemia. In the experiments, the combination of ATRA, ATO and immunotherapy, without conventional chemotherapy, significantly improved control of tumour growth.<\/p>\n<p class=\"wp-block-paragraph\"><strong>What this means for patients<\/strong><\/p>\n<p class=\"wp-block-paragraph\">Analyses of patient samples and data support the relevance of the discovery: greater Pin1 activity was associated with fewer immune cells in the tumour. Pin1 might therefore also serve as a marker for predicting treatment response, a hypothesis that must be tested in dedicated clinical studies.<\/p>\n<p class=\"wp-block-paragraph\">The effectiveness of the combination of ATRA, ATO and anti-PD-1 without conventional chemotherapy has so far been demonstrated in preclinical experimental studies. \u201cThe ability to target Pin1 with drugs already used in clinical practice provides a concrete starting point for developing this strategy. However, dedicated clinical studies will be needed to assess both its safety and its benefits for patients with breast cancer,\u201d said study coordinator Professor Giannino Del Sal.<\/p>\n<p class=\"wp-block-paragraph\"><strong>A perspective beyond breast cancer<\/strong><\/p>\n<p class=\"wp-block-paragraph\">The discovery may also apply to other solid tumours. Fibrosis and low immune activity are features shared by several types of cancer. \u201cIdentifying Pin1 as a link between these two conditions opens the possibility of exploring a common target to overcome resistance to immunotherapy,\u201d Del Sal concluded.<\/p>\n<p class=\"wp-block-paragraph\">Article title:\u00a0\u201cExtracellular matrix stiffness controls Transposable Elements through Pin1 to promote immune evasion in breast cancer\u201d<\/p>\n<p class=\"wp-block-paragraph\">Cancer Discovery \u2013 <a href=\"https:\/\/doi.org\/10.1158\/2159-8290.CD-25-0942?utm_source=brevo&amp;utm_medium=email&amp;utm_campaign=Breast%20cancer%20how%20stiff%20tissue%20makes%20cancer%20invisible%20to%20the%20immune%20system\" target=\"_blank\" rel=\"noopener\">doi.org\/10.1158\/2159-8290.CD-25-0942<\/a>\u00a0publication date: 28 October 2026<\/p>\n","protected":false},"excerpt":{"rendered":"<p>Findings published in Cancer Discovery, a journal of the American Association for Cancer Research, from a study led by Giannino Del Sal of the ICGEB,\u00a0University of Trieste, and the \u201cFondazione Istituto di Oncologia Molecolare\u201d (IFOM), and supported by the AIRC Foundation for Cancer Research.reveal that the Pin1 protein links tumour tissue stiffness to the ability [&hellip;]<\/p>\n","protected":false},"author":4,"featured_media":22449,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":""},"categories":[313,301],"tags":[],"class_list":["post-22476","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-from-our-campuses","category-press-releases"],"acf":[],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v28.6 - 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