Cancer-driver-agnostic targeting of amplified surface proteins identifies MPZL1 for selective CAR-T cell therapy
Abstract Most cancer therapies target genetic alterations driving tumor growth, but many drivers are undruggable or rare, limiting their therapeutic reach. Here, we demonstrate that amplified genes encoding cell surface proteins provide a rich, cancer-driver–agnostic source of targets. We identify MPZL1 (myelin protein zero–like 1), amplified in up to 75% of patients with certain solid tumor types, as abundantly expressed on the surface tumor cells across diverse cancer types while being largely absent from healthy tissues, offering a favorable therapeutic window. We develop a monoclonal antibody targeting MPZL1’s extracellular domain and engineer chimeric antigen receptor (CAR)-T cells that selectively eliminate MPZL1-positive cancer cells in vitro. These CAR-T cells exhibit antitumor activity in human xenograft, autochthonous mouse, and patient-derived tissue explant preclinical models. This work establishes MPZL1 as a viable CAR-T cell target and provides a generalizable framework for exploiting amplified cell surface receptors as broadly applicable therapeutic targets.
Authors
- Luise Butthof
- Judith Feucht (ORCID: https://orcid.org/0000-0002-8745-1079)
- Lio Böse
- Patrick Schmidt (ORCID: https://orcid.org/0000-0002-1917-1446)
- Fee Klupp (ORCID: https://orcid.org/0000-0002-1030-9322)
- Kai Breuhahn (ORCID: https://orcid.org/0000-0002-2462-1229)
- Hendrik Wiethoff (ORCID: https://orcid.org/0000-0002-8450-653X)
- Christos Patsis
- Anna Berthel
- Thomas Longerich (ORCID: https://orcid.org/0000-0001-8888-1030)
- Meggy Suarez‐Carmona (ORCID: https://orcid.org/0000-0002-8892-1546)
- Niels Halama (ORCID: https://orcid.org/0000-0003-0344-6027)
- Darjus F. Tschaharganeh (ORCID: https://orcid.org/0000-0002-2369-5138)
- Lena Wendler-Link
- Peter Schirmacher (ORCID: https://orcid.org/0000-0002-0950-3339)
- Dirk Jaeger (ORCID: https://orcid.org/0000-0002-1276-7802)
- Marco Breinig (ORCID: https://orcid.org/0009-0000-9740-2986)
- Melanie Grimm
- Sonia Jimenez-vazquez
- Matthias M. Gaida (ORCID: https://orcid.org/0000-0003-1499-7772)
- Ilse Hofmann
- Mara Mitstorfer
- Martin Schneider
- Markus Wallwiener
Institutions
- German Cancer Research Center (DE)
- Johannes Gutenberg University Mainz (DE)
- Heidelberg University (DE)
- University Hospital Heidelberg (DE)
- University Medical Center of the Johannes Gutenberg University Mainz (DE)
- National Center for Tumor Diseases (DE)
- University Children's Hospital Tübingen (DE)
- University of Tübingen (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-09-10
- DOI
- https://doi.org/10.1038/s41467-026-77465-5
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 0.00