The clinical successes achieved with immune checkpoint blockers (ICBs) have revolutionized the treatment of multiple advanced-stage malignancies. While these responses are often durable, overall only a subset of patients receiving ICBs has thus far exhibited sustained tumor shrinkage, and adverse effects have been severe in some cases. The absence of dramatic immunotherapeutic responses has been attributed to a variety of factors, including abnormalities in the tumor microenvironment (TME) that induce hypo-perfusion, hypoxia and immunosuppression and hinder ICB delivery. A common abnormality of solid tumors is the accumulation of compressive forces as they grow within a host normal tissue. Compressive forces, caused by the overproduction of stromal cells (e.g., cancer associated fibroblasts or CAFs) and extracellular matrix (ECM) fibers, result in the compression of intratumoral blood vessels. Vessel compression along with the hyper-permeability of the open vessels – owing to the overexpression of pro-angiogenic factors – induce severely compromised vessel functionality (i.e., hypo-perfusion) and tissue hypoxia that affect ICB treatment in multiple ways. To identify strategies to enhance immunotherapy, we have developed a mathematical framework that describes complex interactions among several types of cancer cells, immune cells and endothelial cells known to play crucial roles in tumor progression and response to immunotherapy, as well as molecules involved in tumor angiogenesis and antiangiogenic treatment—processes that have been shown to be modulated by ICB therapy. The model is based on a systems biology approach to connect cellular/subcellular events to overall tumor progression and response to ICBs. It also incorporates mechanisms critical for the efficacy of ICB therapy such as i) the systemic administration of immunotherapeutic drugs to tumors and its modulation by the functionality of the tumor vasculature, ii) the physical barriers to T-cell homing and infiltration into the tumor posed by tumor hypo-perfusion and the dense/stiff TME, iii) the hypoxia-induced overexpression of immune checkpoint molecules, which attenuates the killing potential of effector immune cells, and iv) the TME reprograming, including polarization of macrophages towards an immunosuppressive phenotype. We found that low dose antiangiogenic treatment to normalize the structure of the tumor vasculature can improve ICB therapy when the two treatments are administered sequentially. Furthermore, normalization of ECM and CAFs can further improve perfusion and ICB efficacy, and the benefit is additive when combined with vascular normalization. Model predictions have been validated with our experimental data in murine tumor models that exhibit abundant hyper-permeable and compressed vessels. We conclude that the efficacy of ICB therapy is in large part dictated by tumor vessel functionality, and thus the role of perfusion as a predictive biomarker of response to ICB therapy should be investigated. Citation Format: Triantafyllos Stylianopoulos, Fotios Mpekris, Chrysovalantis Voutouri, James W. Baish, Dan G. Duda, Lance L. Munn, Rakesh K. Jain. Improving immune checkpoint inhibition using tumor microenvironment normalization strategies: Insights from in silico analysis [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr PO054.