Normalization of the tumor microenvironment by harnessing vascular and immune modulation to achieve enhanced cancer therapy

Solid tumors are complex entities that actively shape their microenvironment to create a supportive environment for their own growth. Angiogenesis and immune suppression are two key characteristics of this tumor microenvironment. Despite attempts to deplete tumor blood vessels using antiangiogenic drugs, extensive vessel pruning has shown limited efficacy. Instead, a targeted approach involving the judicious use of drugs at specific time points can normalize the function and structure of tumor vessels, leading to improved outcomes when combined with other anticancer therapies. Additionally, normalizing the immune microenvironment by suppressing immunosuppressive cells and activating immunostimulatory cells has shown promise in suppressing tumor growth and improving overall survival. Based on these findings, many studies have been conducted to normalize each component of the tumor microenvironment, leading to the development of a variety of strategies. In this review, we provide an overview of the concepts of vascular and immune normalization and discuss some of the strategies employed to achieve these goals. New insights into vascular and immune normalization strategies show potential for improving cancer therapy outcomes. In this review, authors discuss the current state of research on vascular and immune normalization in cancer treatment, highlighting the intricate relationship between these two processes. Vascular normalization aims to restore the integrity of tumor blood vessels, improving oxygenation and drug delivery, while immune normalization focuses on modulating the tumor immune microenvironment to suppress immunosuppression and recruit anti-tumoral immune cells. Various methods for achieving vascular normalization include targeting VEGF signaling, Ang-Tie signaling, oncogenic signaling in cancer cells, and even CD4 + T-cells. Strategies for immune normalization involve modulating the myeloid compartment, enhancing effector T cell function through cancer vaccines or immune checkpoint blockade, and using oncolytic viruses to target tumor cells. Combining these approaches may yield even greater efficacy in cancer treatment.