Nanomedicine-Driven Modulation of Reductive Stress for Cancer Therapy.

Redox balance is crucial for cellular function and adaptation to environmental changes, with its disruption playing a key role in the progression of various diseases, including cancer. While oxidative stress caused by excessive reactive oxygen species (ROS) has been widely studied and targeted in cancer therapies, such approaches face significant challenges within the tumor microenvironment. On the opposite end, reductive stress results from an overabundance of reducing equivalents, disrupting normal ROS-dependent signaling pathways and leading to cellular dysfunction. Despite its importance in tumor biology, reductive stress has received less attention than oxidative stress. This group has deliberately driven tumors into a state of reductive stress, thereby exposing unique vulnerabilities and validating a novel therapeutic strategy. Here, the concept and mechanisms of reductive stress is reviewed, introduced methods for detecting it, and discussed its dual role in tumor progression and potential as a therapeutic target. Recent advances in nanomedicine, particularly in the design of functional nanomaterials, enabling precise modulation of cellular redox states are also highlighted. By selectively inducing reductive stress within tumors, nanomedicine offers a promising strategy to exploit tumor vulnerabilities, overcome drug resistance, and improve cancer therapy efficacy.