Extracellular matrix stiffness controls Transposable Elements through Pin1 to promote immune evasion in breast cancer
Breast cancers with a stiff extracellular matrix (ECM) frequently evade immune surveillance through mechanisms that remain incompletely understood. Here, we identify a mechanosensitive immune-evasion pathway governed by the phosphorylation-dependent prolyl isomerase Pin1. We show that ECM rigidity stabilizes Pin1 and promotes its nuclear accumulation in cancer cells, where it preserves heterochromatin organization and nuclear envelope integrity by sustaining HP1α-Lamin interactions, thereby suppressing transposable element (TE) activity. Pin1 loss induces early heterochromatin relaxation and LINE1 reactivation, activating the cGAS/STING/type I interferon pathway. Pin1 depletion further promotes TE-derived neoantigen generation and broadly remodels the tumor immune microenvironment, eliciting innate and adaptive immune responses that enhance tumor clearance. Genetic Pin1 depletion, or pharmacological inhibition with clinically available drugs, sensitizes fibrotic, immune-cold tumors to immune checkpoint blockade. These findings uncover a mechano-genomic mechanism of immune evasion in breast cancer and establish Pin1 as a therapeutic target to restore tumor immunogenicity and improve immunotherapy efficacy.
Authors
- Elena Campaner (ORCID: https://orcid.org/0000-0002-0481-3522)
- Giulia Maria Piperno (ORCID: https://orcid.org/0000-0003-4467-7315)
- Anna Renzi (ORCID: https://orcid.org/0009-0004-1029-9330)
- Zeno Lavagnino (ORCID: https://orcid.org/0000-0002-7247-8084)
- Fiamma Mantovani (ORCID: https://orcid.org/0000-0002-1731-3519)
- Serena Torrini (ORCID: https://orcid.org/0000-0003-1117-5992)
- Rebecca Bertolio (ORCID: https://orcid.org/0000-0001-5451-7820)
- Valentina Guarneri (ORCID: https://orcid.org/0000-0002-2375-8397)
- Sara Donzelli (ORCID: https://orcid.org/0000-0002-8529-2895)
- Francesco Napoletano (ORCID: https://orcid.org/0000-0002-0910-3167)
- Marcin Braun (ORCID: https://orcid.org/0000-0003-3804-7042)
- Galina V. Beznoussenko (ORCID: https://orcid.org/0000-0002-1876-4098)
- Francesco Ferrari (ORCID: https://orcid.org/0000-0002-9811-3753)
- Giovanni Blandino (ORCID: https://orcid.org/0000-0002-6970-2241)
- Tito Panciera (ORCID: https://orcid.org/0000-0002-9272-5716)
- Davide Selvestrel (ORCID: https://orcid.org/0009-0007-8959-6670)
- Stefano Piccolo (ORCID: https://orcid.org/0000-0002-1600-3092)
- Francesca Zanconato (ORCID: https://orcid.org/0000-0002-1805-8249)
- Giulia Canarutto (ORCID: https://orcid.org/0000-0001-5010-7269)
- Hanna Romańska (ORCID: https://orcid.org/0000-0002-2328-710X)
- Antonio Rosato (ORCID: https://orcid.org/0000-0002-5263-8386)
- Giannino Del Sal (ORCID: https://orcid.org/0000-0003-2185-6003)
- Roberta Sommaggio (ORCID: https://orcid.org/0000-0002-5682-5867)
- Luca Triboli (ORCID: https://orcid.org/0000-0002-1261-0637)
- Giovanni Sorrentino (ORCID: https://orcid.org/0000-0001-8628-8778)
- Valeria Cancila (ORCID: https://orcid.org/0000-0002-9502-1191)
- Federica Benvenuti (ORCID: https://orcid.org/0000-0002-1908-8052)
- Lucía López (ORCID: https://orcid.org/0000-0003-0742-647X)
- Arianna Bertossi (ORCID: https://orcid.org/0000-0001-6088-7318)
- Silvia Marsoni (ORCID: https://orcid.org/0000-0002-5361-7122)
- Maria Vittoria Dieci (ORCID: https://orcid.org/0000-0002-3967-9861)
- Gaia Griguolo (ORCID: https://orcid.org/0000-0002-8782-4509)
- Federica Lucini (ORCID: https://orcid.org/0000-0001-8515-193X)
- Silvano Piazza (ORCID: https://orcid.org/0000-0002-7156-5434)
- Claudio Tripodo (ORCID: https://orcid.org/0000-0002-0821-6231)
- Paulina Nastały (ORCID: https://orcid.org/0000-0003-4811-4915)
- Alessandra Rustighi (ORCID: https://orcid.org/0000-0001-5937-9113)
- Anna Tosi (ORCID: https://orcid.org/0000-0002-4890-0169)
- Alessia Chiofalo (ORCID: https://orcid.org/0009-0003-2809-5064)
- Giovanni Lembo (ORCID: https://orcid.org/0009-0001-6150-0573)
- Matteo Marchionni (ORCID: https://orcid.org/0000-0002-1163-3466)
- Melina Albano (ORCID: https://orcid.org/0009-0001-5607-2201)
- Dominik Paprocki (ORCID: https://orcid.org/0009-0005-4720-4339)
- SUVARNA CHATTERJEE (ORCID: https://orcid.org/0009-0003-9396-8263)
- Daria Dobrovic (ORCID: https://orcid.org/0009-0007-5017-397X)
- Melpomenie Guissouegou Doubi (ORCID: https://orcid.org/0009-0006-9694-0874)
Institutions
- University of Udine (IT)
- University of Padua (IT)
- University of Trieste (IT)
- University of Milan (IT)
- Istituto Oncologico Veneto (IT)
- IFOM (IT)
- Medical University of Lodz (PL)
- Instituto Nazionale Tumori Regina Elena (IT)
- Gdańsk Medical University (PL)
- University of Palermo (IT)
- International Centre for Genetic Engineering and Biotechnology (IT)
Publication Details
- Journal
- Cancer Discovery
- Published
- 2026-10-28
- DOI
- https://doi.org/10.1158/2159-8290.cd-25-0942
- Primary Topic
- Signaling Pathways in Disease
- Type
- article
- Field-Weighted Citation Impact
- 0.00