Targeting ERO1α triggers tumor immunosurveillance in triple-negative breast cancer
10 affiliations
- 1Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy; Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, Italy
- 2Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
- 3Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy; Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy
- 4IFOM ETS, The AIRC Institute of Molecular Oncology, Milan, Italy
- 5Cogentech SRL Benefit Corporation, Milan, 20139, Italy
- 6Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, Italy
- 7Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy; Bioinformatics Core Unit, Institute of Oncology Research (IOR), Bellinzona, Switzerland
- 8U.O. Patologia Mammaria e Tumori Cerebrali, Azienda Socio-Sanitaria Territoriale, Cremona, Italy
- 9Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy; IRCCS Humanitas Research Hospital, Milan, Italy
- 10Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy; Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, Italy; Corresponding author. Istituto di Ricerche Farmacologiche Mario Negri IRCCS Via Mario Negri 2, 20156, Milano, Italy.
Abstract
Triple-negative breast cancer (TNBC) remains a highly aggressive malignancy with limited responsiveness to immune checkpoint blockade. Here, we identify endoplasmic reticulum oxidoreductase 1 alpha (ERO1α; ERO1A), a key regulator of oxidative protein folding, as a determinant of tumor immunogenicity and immunotherapy response in TNBC. Unbiased proteomic profiling demonstrated that ERO1α deficiency remodels the TNBC glycoproteome, leading to enrichment of pathways associated with immune signaling. Although ERO1α loss did not affect tumor cell growth, it reshaped the immune tumor microenvironment, enhancing antigen presentation, altering myeloid-cell composition, and modulating PD-1/PD-L1–associated signaling. Functionally, ERO1α deficiency sensitized otherwise refractory TNBC tumors to PD-1 blockade, resulting in durable tumor regression in immunocompetent hosts. In contrast, ERO1α deletion in bone marrow–derived immune cells had minimal effects on tumor growth or therapeutic response, supporting an ERO1α tumor-intrinsic mechanism. Pharmacologic inhibition of ERO1α with the novel small-molecule inhibitor I29 phenocopied ERO1α genetic deletion and enhanced the efficacy of anti–PD-1 therapy. Together, these findings identify ERO1α-dependent glycoproteome remodeling as a regulator of antitumor immunity and a therapeutically actionable mechanism of immune checkpoint responsiveness in TNBC.
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BibTeX
@article{cherubini2026targeting,
title = {{Targeting ERO1α triggers tumor immunosurveillance in triple-negative breast cancer}},
author = {Alessandro Cherubini and Ersilia Varone and Sara Irene Malandrin and Alice Marrazza and Giorgia Maria Renna and Serena Germani and Stefano Fumagalli and Angela Bachi and Angela Cattaneo and Michele Retini and Giovanni Piersanti and Marco Bolis and Ilaria Craparotta and Arianna Vallerga and Chiara Grasselli and Manuela Milani and Daniele Generali and Augusto Bleve and Ester Zito},
journal = {Redox Biology},
year = {2026},
month = oct,
doi = {10.1016/j.redox.2026.104451},
url = {https://doi.org/10.1016/j.redox.2026.104451},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - Targeting ERO1α triggers tumor immunosurveillance in triple-negative breast cancer
AU - Alessandro Cherubini
AU - Ersilia Varone
AU - Sara Irene Malandrin
AU - Alice Marrazza
AU - Giorgia Maria Renna
AU - Serena Germani
AU - Stefano Fumagalli
AU - Angela Bachi
AU - Angela Cattaneo
AU - Michele Retini
AU - Giovanni Piersanti
AU - Marco Bolis
AU - Ilaria Craparotta
AU - Arianna Vallerga
AU - Chiara Grasselli
AU - Manuela Milani
AU - Daniele Generali
AU - Augusto Bleve
AU - Ester Zito
PY - 2026
DA - 2026/10/23
JO - Redox Biology
DO - 10.1016/j.redox.2026.104451
UR - https://doi.org/10.1016/j.redox.2026.104451
AB - Triple-negative breast cancer (TNBC) remains a highly aggressive malignancy with limited responsiveness to immune checkpoint blockade. Here, we identify endoplasmic reticulum oxidoreductase 1 alpha (ERO1α; ERO1A), a key regulator of oxidative protein folding, as a determinant of tumor immunogenicity and immunotherapy response in TNBC. Unbiased proteomic profiling demonstrated that ERO1α deficiency remodels the TNBC glycoproteome, leading to enrichment of pathways associated with immune signaling. Although ERO1α loss did not affect tumor cell growth, it reshaped the immune tumor microenvironment, enhancing antigen presentation, altering myeloid-cell composition, and modulating PD-1/PD-L1–associated signaling. Functionally, ERO1α deficiency sensitized otherwise refractory TNBC tumors to PD-1 blockade, resulting in durable tumor regression in immunocompetent hosts. In contrast, ERO1α deletion in bone marrow–derived immune cells had minimal effects on tumor growth or therapeutic response, supporting an ERO1α tumor-intrinsic mechanism. Pharmacologic inhibition of ERO1α with the novel small-molecule inhibitor I29 phenocopied ERO1α genetic deletion and enhanced the efficacy of anti–PD-1 therapy. Together, these findings identify ERO1α-dependent glycoproteome remodeling as a regulator of antitumor immunity and a therapeutically actionable mechanism of immune checkpoint responsiveness in TNBC.
SN - 2213-2317
ER -