Cell surface thiol-disulfide regulation in cancer: Mechanisms, implications, and theranostic strategies

Area of Science:

• Biochemistry
• Oncology
• Molecular Biology

Background:

• Cancer cells exhibit disrupted redox homeostasis, contributing to tumor progression, metastasis, and therapy resistance.
• Elevated reactive oxygen species (ROS) in cancer are counterbalanced by antioxidant systems like thioredoxin-1 (TXN1)/thioredoxin reductase-1 (TXNRD1) and protein disulfide isomerases (PDIs).
• These systems function at the cell surface, remodeling redox states to create microenvironments that favor cancer cell invasion and treatment resistance.

Purpose of the Study:

• To review how TXN1, TXNRD1, and PDIs regulate cell surface thiol-disulfide balance in cancer.
• To explore the exploitation of these redox alterations for theranostic applications.
• To highlight extracellular redox regulation as a target for next-generation cancer theranostics.

Main Methods:

• Literature review summarizing evidence from multiple cancer types (breast, colon, lung, prostate, B-cell chronic lymphocytic leukemia).
• Analysis of the role of TXN1 and PDI overexpression in altered exofacial thiol-disulfide states.
• Discussion of thiol-mediated targeting strategies and redox-responsive approaches.

Main Results:

• Overexpression of TXN1 and PDIs leads to altered exofacial thiol-disulfide states, a reproducible feature of cancer progression.
• These redox alterations create reduced extracellular microenvironments that promote cancer cell invasion, metastasis, and therapy resistance.
• Altered surface redox states can be exploited for selective delivery of therapeutics to cancer cells.

Conclusions:

• Extracellular redox regulation by TXN1 and PDI is a key tumor-associated feature.
• Surface redox phenotypes can serve as biomarkers for cancer progression.
• Targeting extracellular redox regulation offers novel theranostic opportunities beyond antigen-specific strategies.