Combining microenvironment normalization strategies to improve cancer immunotherapy

Significance Immunotherapy has changed the standard of care in cancer treatment, but an estimated 87% of patients currently do not derive long-term benefit from immune checkpoint blocker monotherapy. Therefore, new therapeutic strategies are needed to improve the response rates in patients who are resistant to immune checkpoint inhibition. We have developed a mathematical framework to determine how tumor microenvironment normalization strategies—specifically, vascular and stroma normalization—might improve immunotherapy efficacy. By incorporating complex interactions among various types of cancer cells, immune cells, stromal cells, and the vasculature, as well as physical mechanisms, we provide guidelines for designing effective combinatorial therapeutic strategies and point out areas for future investigation.