Reductive stress in cancer immunology and targeted therapy

Abstract

Reductive stress is characterized by the excessive accumulation of cellular reducing equivalents, leading to the disruption of cellular redox homeostasis and a shift toward a reductive intracellular environment. Immune cells exhibit particularly dynamic redox modulation to adapt to activation and differentiation processes during immune responses, such as tumor recognition and destruction. Unlike their immune counterparts, tumor cells employ a specific metabolic mode for uncontrolled proliferation and survival, which may also lead to a shift in the intracellular redox balance. While extensive research has focused on oxidative stress during the immune response and cancer treatment, studies on reductive stress are still in their infancy. This review summarizes the generation process of reductive stress and its impact on cellular function, detailing its mechanisms in immune cells and various cancers, as well as its relevance to cancer treatment. The aim of this study is to explore new avenues for cancer immunotherapy from the perspective of reductive stress.

1. Introduction

Redox homeostasis is a balance between oxidative and reductive biochemical reactions; it is necessary for maintaining the fundamental functionality of a cell and has a central role in human health. Disruptions in cellular redox homeostasis can cause various diseases, including cardiovascular diseases, diabetes, Alzheimer’s disease (AD), and cancers [1–3]. Reactive oxygen species (ROS), which are byproducts of cellular metabolic activities, include superoxide anion radicals, hydrogen peroxides, and other oxygen-containing radicals. Owing to their unpaired electrons, ROS exhibit high oxidative reactivity. At low concentrations, ROS act as signaling molecules to regulate various biological processes in cells, whereas excessive ROS accumulation leads to cytotoxicity, referred to as oxidative stress. Under these conditions, ROS within the cell uncontrollably over-oxidize lipids, proteins, and nucleic acids, resulting in the formation of lipid peroxides, aberrantly modified proteins with thiol groups (such as disulfide bonds), and 8-oxo-guanine complexes [4]. These products cause irreversible damage to biomacromolecules and subsequently trigger various cellular death mechanisms, including senescence, apoptosis, autophagy, and ferroptosis [5].

Immunotherapy represents a distinct approach to conventional cancer treatments by which the immune system is activated to eliminate tumor cells consistently and effectively. However, the dysregulated metabolic activity of tumor cells often creates a unique tumor microenvironment (TME) that suppresses immune cell activation and infiltration, rendering the immune system incapable of eliminating tumor cells. Imbalances in redox homeostasis can differentially affect malignant progression, immune surveillance and even the formation of an immunosuppressive TME. Therefore, targeting redox imbalances represents a promising avenue for enhancing the efficacy of immunotherapy.

Although oxidative stress in cancer has been extensively studied, the opposite of redox homeostasis—reductive stress—remains overlooked, despite its identification as a cause of cell death as early as 1989 [6]. Unlike oxidative stress, reductive stress is not solely defined by reduced ROS levels but rather by the excessive accumulation of reducing equivalents. The term “reducing equivalent” refers to the minimal molar amount of a substance that can react with an oxidizing agent in redox reactions. Its overaccumulation has been acknowledged as a hallmark of cellular reductive stress. This is exemplified by the increased ratios of nicotinamide adenine nucleotide hydrate (NADH)/nicotinamide adenine dinucleotide (NAD+), nicotinamide adenine nucleotide phosphate (NADPH)/nicotinamide adenine nucleotide phosphate (NADP+), and glutathione/glutathione disulfide (GSH/GSSG) (Figure 1). As previously discussed, the cellular reducing capacity comprises a diverse array of reductants integral to numerous metabolic pathways, each governed by distinct regulatory mechanisms. Consequently, reductive stress cannot be simplistically conceptualized as merely the inverse of oxidative stress, despite both disrupting redox homeostasis. Typically, reductive stress exerts detrimental cellular effects—manifesting as aberrant signaling, protein misfolding, mitochondrial dysfunction, and metabolic dysregulation—which culminate in suppressed proliferation or cell death [3,7–10]. However, a paradoxical divergence emerges within cancer-immune dynamics. Both immune and tumor cells undergo metabolic reprogramming to fuel proliferation or differentiation within varying tissue microenvironments. Thus, reductive stress functions as a context-dependent modulator of cancer-immune interactions, and its net impact varies with tumor type, metabolic niche, and immune cell subset. It can simultaneously inhibit tumor cell proliferation, impair the immunosuppressive function of regul