Selective tubulin-binding drugs induce pericyte phenotype switching and anti-cancer immunity
The intratumoral immune milieu is crucial for the success of anti-cancer immunotherapy. We show here that stromal modulation by the tubulin-binding anti-cancer drugs combretastatin A4 (CA-4) and eribulin improved tumor perfusion and anti-tumor immunity. This was achieved by reverting highly proliferative, angiogenic pericytes into a quiescent, contractile state which durably normalized the vascular bed and reduced hypoxia in mouse models of pancreatic neuroendocrine cancer, breast cancer and melanoma. The crucial event in pericyte phenotype switching was RhoA kinase activation, which distinguished CA-4 and eribulin effects from other anti-mitotic drugs such as paclitaxel and vinorelbine. Importantly, eribulin pre-treatment sensitized tumors for adoptive T cell therapy or checkpoint inhibition resulting in effector cell infiltration and better survival outcomes in mice. In breast cancer patients, eribulin neoadjuvant treatment induced pericyte maturity and RhoA kinase activity indicating similar vessel remodeling effects as seen in mice. Moreover, a contractile pericyte signature was associated with overall better survival outcome in two independent breast cancer cohorts. This underscores the potential of re-purposing specific anti-cancer drugs to enable synergistic complementation with emerging immunotherapies.
Authors
- Andrew Redfern (ORCID: https://orcid.org/0000-0001-6728-8713)
- Lisa Spalding (ORCID: https://orcid.org/0000-0002-3885-9625)
- Bruce A. Littlefield
- Judith A. Ermer (ORCID: https://orcid.org/0000-0003-0234-9620)
- Edward Bastow
- Erik W. Thompson (ORCID: https://orcid.org/0000-0002-9723-4924)
- Suraj Sakaram (ORCID: https://orcid.org/0000-0003-1841-1898)
- Bo He (ORCID: https://orcid.org/0000-0003-0741-0662)
- Jordi Canes (ORCID: https://orcid.org/0000-0002-1309-5745)
- Javier Cortés (ORCID: https://orcid.org/0000-0001-7623-1583)
- Mafalda Oliveira (ORCID: https://orcid.org/0000-0001-9152-8799)
- Phillip K. Darcy (ORCID: https://orcid.org/0000-0002-5303-9561)
- Ruth Ganß (ORCID: https://orcid.org/0000-0002-5551-045X)
- Ji Li (ORCID: https://orcid.org/0000-0003-0931-5562)
- Aleix Prat (ORCID: https://orcid.org/0000-0003-2377-540X)
- Zhijie Li (ORCID: https://orcid.org/0000-0002-0662-6800)
- C. Redfern
- Kira H Wood
Institutions
- Medigene (Germany) (DE)
- Translational Research Institute (AU)
- Jinan University (CN)
- Queensland University of Technology (AU)
- The University of Melbourne (AU)
- The University of Western Australia (AU)
- Harry Perkins Institute of Medical Research (AU)
- Peter MacCallum Cancer Centre (AU)
- Fiona Stanley Hospital (AU)
- Southern University of Science and Technology (CN)
- MedSIR (Spain) (ES)
- Hospital Clínic de Barcelona (ES)
- Vall d'Hebron Hospital Universitari (ES)
- Solti (ES)
- Eisai (United States) (US)
- Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES)
- Shenzhen Second People's Hospital (CN)
- Vall d'Hebron Institute of Oncology (ES)
- Universitat de Barcelona (ES)
- Universidad Europea de Madrid (ES)
Publication Details
- Journal
- EMBO Molecular Medicine
- Published
- 2025-03-26
- DOI
- https://doi.org/10.1038/s44321-025-00222-6
- Citations
- 10
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 10.45
Funders
- Worldwide Cancer Research
- Australian Government
- Cancer Australia
- National Health and Medical Research Council
- Cancer Council Western Australia
- Eisai Incorporated