Characteristics of the Tumor Microenvironment That Influence Immune Cell Functions: Hypoxia, Oxidative Stress, Metabolic Alterations

SIMPLE SUMMARY: For decades nearly all cancer patients were treated with cytotoxic chemotherapy, killing any rapidly dividing cell in the body. More recently, researchers have been studying the immune system’s response to cancer and have developed a novel class of drugs that stimulate the body’s own response to tumors. This class of immunotherapy drugs primarily involve T-cells, immune cells that target and destroy cancer cells. While these drugs can lead to remarkable and sustained response, most patients do not respond. Understanding the resistance mechanisms in non-responding tumors is now an active area of investigation. In this review, we explore a host of factors in the tumor microenvironment, the cellular and molecular space within tumor tissue, to identify possible culprits of immunotherapy resistance. Specifically, the downstream effects of low oxygen and metabolic byproducts in the tumor microenvironment have been associated with immune cell dysfunction. Importantly, targeting these pathways may offer promising therapies to improve the response to current immunotherapy. ABSTRACT: Immunotherapy (IMT) is now a core component of cancer treatment, however, many patients do not respond to these novel therapies. Investigating the resistance mechanisms behind this differential response is now a critical area of research. Immune-based therapies, particularly immune checkpoint inhibitors (ICI), rely on a robust infiltration of T-cells into the tumor microenvironment (TME) for an effective response. While early efforts relied on quantifying tumor infiltrating lymphocytes (TIL) in the TME, characterizing the functional quality and degree of TIL exhaustion correlates more strongly with ICI response. Even with sufficient TME infiltration, immune cells face a harsh metabolic environment that can significantly impair effector function. These tumor-mediated metabolic perturbations include hypoxia, oxidative stress, and metabolites of cellular energetics. Primarily through HIF-1-dependent processes, hypoxia invokes an immunosuppressive phenotype via altered molecular markers, immune cell trafficking, and angiogenesis. Additionally, oxidative stress can promote lipid peroxidation, ER stress, and Treg dysfunction, all associated with immune dysregulation. Finally, the metabolic byproducts of lipids, amino acids, glucose, and cellular energetics are associated with immunosuppression and ICI resistance. This review will explore these biochemical pathways linked to immune cell dysfunction in the TME and highlight potential adjunctive therapies to be used alongside current IMT.