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

Abstract

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.

Microphysiological systems as models for immunologically ‘cold’ tumors

“…Therefore, ‘cold’ and ‘altered’ tumors typically exhibit limited clinical benefits from immune checkpoint inhibitors. The vasculature in tumors exhibits structural disorganization and functional abnormalities, particularly in ‘cold’ tumors ( Choi and Jung, 2023 ). ‘cold’ tumors often suffer from impaired blood perfusion, restricting the effective delivery of therapeutics and cytotoxic immune cells, leading to hypoxia—a hallmark of the abnormal TME inducing immunosuppression ( Schaaf et al, 2018 ).…”

“…Adjuvant therapies, such as dendritic cell, mRNA, and peptide-based vaccinations, aim to boost the patient’s anticancer immunity by stimulating antigen-specific CD8 + T cells ( Saxena et al, 2021 ). These mechanisms have the potential to convert ‘cold’ tumors into immunogenic ‘hot’ tumors by generating potent cytotoxic T lymphocyte responses capable of eradicating tumors ( Choi and Jung, 2023 ). Additional strategies to elicit a robust immune response in these tumors involve agonistic antibodies to promote co-stimulation (e.g., via CD137 (4-1BB), OX40, and GITR), cytokine therapy (e.g., IL-2, IL-12, IFN-γ), bispecific antibodies, and oncolytic viruses ( Mu et al, 2023 ).…”

Advances and Challenges in Targeting TGF-β Isoforms for Therapeutic Intervention of Cancer: A Mechanism-Based Perspective

“…This hypoxic niche, in conjunction with the inherent metabolic rewiring of cancer cells, elevates HIFs in tumor cells that cooperatively induce the transcription of VEGF and TGF-β1, both serving to promote angiogenesis through binding to and stimulating the growth of endothelial cells ( Figure 7 ) [ 356 , 359 , 360 , 361 , 362 ]. However, this angiogenic signal is so strong that tumors often become over-vascularized, causing contorted vasculature and a subsequent increase in hypoxia from poor or stagnant circulation [ 363 ]. Stasis from stagnant blood flow promotes thrombosis [ 364 ] and hence the release and activation of platelet-derived TGF-β1.…”

Engineering tumor-oxygenated nanomaterials: advancing photodynamic therapy for cancer treatment

“…In the TME, abnormal blood vessels often develop, leading to poor blood flow and limited drug delivery to the tumor site. However, by targeting these abnormal vessels and restoring their functionality, tumor vasculature normalization can improve the delivery of therapeutic agents to the tumor ( Choi and Jung, 2023 ).…”