Model reveals strategies to modify the tumor microenvironment and improve cancer therapy
· Medical Xpressby Brian Burns, Mass General Brigham
edited by Sadie Harley, reviewed by Andrew Zinin
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Researchers from Mass General Brigham and the University of Cyprus have developed a mathematical model to better understand how the tumor microenvironment affects the delivery and effectiveness of a new type of cancer therapy called an immunomodulatory antibody-drug conjugate (IM-ADC). The work is published in the Journal for ImmunoTherapy of Cancer.
The model, developed by a team led by Rakesh Jain, Ph.D., of the Department of Radiation Oncology at Mass General Brigham, incorporates key features of the tumor microenvironment, including abnormal blood vessels, elevated interstitial fluid pressure, immune cell activity, drug transport and tumor-draining lymph nodes.
The researchers used the model to assess HE-S2, an experimental IM-ADC therapy that combines an anti-PD-L1 antibody with an immune-stimulating payload called D18.
By fitting the model to published mouse studies, the researchers were able to reproduce observed tumor responses and explore biological processes that cannot easily be measured experimentally.
The team found that HE-S2 was more effective than either of its individual components alone.
The model also suggests a positive feedback loop: As the therapy shrinks the tumor, interstitial fluid pressure decreases, improving drug delivery and further enhancing treatment effectiveness. If taken too far, however, this normalization process can reduce vascular permeability. ADCs are large-molecule therapeutics that need pores at least 40 nanometers in size to reach their target.
The results support strategies aimed at "normalizing" the tumor microenvironment before ADC treatment, such as improving blood vessel function while preserving sufficient vascular permeability to allow large antibody-based therapies to penetrate tumors.
Publication details
Constantinos Harkos et al, Mechanistic modeling of tumor immune microenvironment reveals strategies to enhance antibody-drug conjugates' efficacy, Journal for ImmunoTherapy of Cancer (2026). DOI: 10.1136/jitc-2026-015357
Journal information: Journal for ImmunoTherapy of Cancer
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