2025
EMBO Mol Med. 2025 May;17(5):1071-1100. doi: 10.1038/s44321-025-00222-6.
Selective tubulin-binding drugs induce pericyte phenotype switching and anti-cancer immunity
Cancer Microenvironment Laboratory, Harry Perkins Institute of Medical Research, Centre for Medical Research, The University of Western Australia, Perth, WA, Australia. Department of Geriatrics and Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Guangdong, P. R. China. INSiGENe Pty Ltd, UGenome, Tucson, AZ, USA. Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. Harry Perkins Institute of Medical Research, Centre for Medical Research, The University of Western Australia, Perth, WA, Australia. SOLTI Cancer Research Group, Barcelona, Spain. Medical Oncology Department, Vall d'Hebron University Hospital, Barcelona, Spain. Breast Cancer Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. Medical Oncology Department, Hospital Clinic of Barcelona, Barcelona, Spain. Translational Genomics and Targeted Therapies in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain. Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain. Medica Scientia Innovation Research (MEDSIR)-Oncoclínicas&Co, Jersey City, NJ, USA. Medica Scientia Innovation Research (MEDSIR)-Oncoclínicas&Co, Sao Paulo, Brazil. International Breast Cancer Center (IBCC), Pangaea Oncology, Quiron Group, Barcelona, Spain. Faculty of Biomedical and Health Sciences, Department of Medicine, Universidad Europea de Madrid, Madrid, Spain. IOB Madrid, Institute of Oncology, Hospital Beata María Ana, Madrid, Spain. School of Biomedical Sciences and Centre for Genomics and Personalised Health, Faculty of Health, Queensland University of Technology (QUT) and Translational Research Institute, Brisbane, Australia. Eisai Inc., Cambridge, MA, USA. Fiona Stanley Hospital, Perth, WA, Australia. Cancer Microenvironment Laboratory, Harry Perkins Institute of Medical Research, Centre for Medical Research, The University of Western Australia, Perth, WA, Australia.
Service type: Stock strains
Abstract
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. Keywords: Angiogenesis; Microtubule-binding Drugs; Pericytes; Rho Kinase; Tumor Immunity.
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