Reactive Oxygen Species: From Tumorigenesis to Therapeutic Strategies in Cancer

Abstract

Background: Reactive oxygen species (ROS), a class of highly reactive molecules, are closely linked to the pathogenesis of various cancers. While ROS primarily originate from normal cellular processes, external stimuli can also contribute to their production. Cancer cells typically exhibit elevated ROS levels due to disrupted redox homeostasis, characterized by an imbalance between antioxidant and oxidant species. ROS play a dual role in cancer biology: at moderate levels, they facilitate tumor progression by regulating oncogenes and tumor suppressor genes, inducing mutations, promoting proliferation, extracellular matrix remodeling, invasion, immune modulation, and angiogenesis. However, excessive ROS levels can cause cellular damage and initiate apoptosis, necroptosis, or ferroptosis.

Methods: This review explores molecular targets involved in redox homeostasis dysregulation and examines the impact of ROS on the tumor microenvironment (TME). Literature from recent in vitro and in vivo studies was analyzed to assess how ROS modulation contributes to cancer development and therapy.

Results: Findings indicate that ROS influence cancer progression through various pathways and cellular mechanisms. Targeting ROS synthesis or enhancing ROS accumulation in tumor cells has shown promising anticancer effects. These therapeutic strategies exhibit significant potential to impair tumor growth while also interacting with elements of the TME.

Conclusion: The ROS serve as both promoters and suppressors of cancer depending on their intracellular concentration. Their complex role offers valuable opportunities for targeted cancer therapies. While challenges remain in precisely modulating ROS for therapeutic benefit, they hold promise as synergistic agents alongside conventional treatments, opening new avenues in cancer management.

Keywords: cancer; homeostatic dysregulation; reactive oxygen species; signal transducer; tumorigenesis.

FIGURE 1

The figure illustrates the differential level of ROS in three cellular contexts‐normal, tumor‐promoting, and tumor‐suppressing conditions. In normal conditions, ROS levels are maintained at a balanced state essential for normal homeostasis. Under tumor‐promoting conditions, moderately increased ROS levels are observed along with increased metabolism, growth signaling, and antioxidant inhibition. In tumor‐suppressing conditions, elevated ROS levels promote DNA damage and cell death, mostly through apoptosis.

FIGURE 2

Schematic representation of the molecular mechanism of the KEAP‐Nrf2 ARE pathway: Under normal conditions, the Nrf2 remains attached to KEAP, together with Cul3, and is subjected to ubiquitination and proteasomal degradation. Under oxidative stress, the cysteine residues in KEAP oxidize, causing Nrf2 to dissociate and translocate into the nucleus where it binds to MAF proteins and induces the expression of anti‐oxidative and cytoprotective entities; ARE, antioxidant response element; Cul3, Cullin 3; KEAP1, Kelch‐like ECH‐associated protein 1; MAF, small musculoaponeurotic fibrosarcoma oncogene homolog; Nrf2, nuclear factor erythroid‐2‐related factor 2.

FIGURE 3

The dynamic and complex tumor microenvironment includes different cellular components such as cancer cells, immune cells, CAFs, and endothelial cells, along with non‐cellular elements such as the ECM.

FIGURE 4

Impact of ROS on tumor microenvironment; (i) immune cell modulation; (ii) ROS‐mediated ECM remodeling; (iii) ROS‐mediated angiogenesis; (iv) epithelial to mesenchymal transition (EMT).