A research team led by Prof. WANG Likun at the Institute of Biophysics of the Chinese Academy of Sciences has identified divalent manganese ions (Mn²⁺) as powerful and selective activators of IRE1α (inositol-requiring enzyme 1α), a critical sensor in the unfolded protein response (UPR) pathway. 

Published in iScience on July 15, the study reveals that Mn²⁺ hyperactivates IRE1α, triggering pro-apoptotic signaling and effectively suppressing tumor growth, suggesting a promising new avenue for cancer therapy.

IRE1α plays a vital role in maintaining endoplasmic reticulum (ER) homeostasis during cellular stress. However, sustained or excessive activation of IRE1α under chronic ER stress can induce cell death through downstream pathways such as regulated IRE1α-dependent decay (RIDD) and JNK signaling. Whether artificially enhancing IRE1α activation could be exploited to inhibit tumor progression has remained largely unexplored.

In this study, the researchers demonstrated that Mn²⁺ significantly enhances IRE1α phosphorylation and oligomerization under ER stress conditions, thereby activating pro-death pathways such as RIDD and JNK and inducing apoptosis in breast cancer cells.

Mechanistic studies further showed that Mn²⁺ directly binds to the cytosolic domain of IRE1α, stabilizing the protein and boosting both its kinase and RNase activity. This provides a molecular foundation for its pro-apoptotic effect.

In vivo, intratumoral injection of Mn²⁺ markedly suppressed tumor growth in an orthotopic breast cancer model. Crucially, this anti-tumor effect was completely abolished in IRE1α-deficient tumors, confirming that the therapeutic benefit is strictly IRE1α-dependent.

Following Mn²⁺ treatment, tumor tissues showed significantly elevated levels of JNK phosphorylation and apoptosis, while treated mice exhibited no significant weight loss or adverse effects, suggesting a favorable safety profile in the short term.

This study is the first to propose a "pro-activation" approach to targeting IRE1α for cancer therapy, rather than the conventional strategy of inhibition. This approach could be particularly effective in tumors with intrinsically high IRE1α activity and opens up new possibilities for harnessing the UPR signaling network in oncology.

Given that Mn²⁺ compounds are already used clinically such as MRI contrast agents, these findings support the potential repurposing of Mn²⁺ as a tumor-targeting therapeutic agent. With further refinement, Mn²⁺-based therapies could become a new class of anti-cancer treatments aimed at selectively triggering cell death in tumors via IRE1α hyperactivation.

Schematic illustration of the mechanism by which manganese hyperactivates IRE1α to suppress tumor growth (Image by WANG Likun's group)