Selective tubulin-binding drugs induce pericyte phenotype switching and anti-cancer immunity

Selective tubulin-binding drugs induce pericyte phenotype switching and anti-cancer immunity

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...

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Main Authors: Bo He, Kira H Wood, Zhi-jie Li, Judith A Ermer, Ji Li, Edward R Bastow, Suraj Sakaram, Phillip K Darcy, Lisa J Spalding, Cameron T Redfern, Jordi Canes, Mafalda Oliveira, Aleix Prat, Javier Cortes, Erik W Thompson, Bruce A Littlefield, Andrew Redfern, Ruth Ganss
Format: Article
Language:English
Published: Springer Nature 2025-03-01
Series:EMBO Molecular Medicine
Subjects:
Angiogenesis
Pericytes
Microtubule-binding Drugs
Tumor Immunity
Rho Kinase
Online Access:https://doi.org/10.1038/s44321-025-00222-6
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Summary: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.
ISSN:1757-4684

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