Recent research identifies serglycin as a major driver of LAG3+ Treg differentiation in gastric cancer. This tumor-derived proteoglycan facilitates immune evasion by manipulating the microenvironment. Specifically, it acts through the CD44 receptor, which regulatory T cells (Tregs) express at high levels. By targeting this signaling axis, clinicians might eventually improve the effectiveness of existing cancer treatments.

Mechanisms of LAG3+ Treg Differentiation

Furthermore, analysis of single-cell RNA-sequencing data confirms that serglycin levels correlate significantly with Treg enrichment. Mechanistically, serglycin activates the CD44/TGFβRI/Smad3 signaling pathway. Consequently, this activation promotes cellular glycolysis while facilitating the clearance of reactive oxygen species (ROS). Therefore, these metabolic changes are crucial for stabilizing the LAG3 protein within the immunosuppressive tumor microenvironment.

Specifically, the reduction in cellular oxidation attenuates the M171 modification of LAG3. This change enhances LAG3 dimerization and disrupts its interaction with the ubiquitin ligase PELI1. As a result, LAG3 avoids K48-linked ubiquitination and subsequent degradation. Moreover, these findings suggest that the metabolic state of the T cell directly controls the stability of its inhibitory receptors.

Targeting the Serglycin-CD44 Axis

Collectively, these findings identify a serglycin-CD44-mediated metabolic cascade that functions as a critical driver of LAG3+ Treg differentiation. Blocking this pathway in pre-clinical models has successfully relieved immunosuppression and inhibited tumor progression. Therefore, targeting this axis offers a promising strategy for enhancing immunotherapy. For instance, combining serglycin inhibitors with LAG3 blockades might yield superior results in patients with gastric malignancies.

Frequently Asked Questions

What is the role of serglycin in gastric cancer?

Serglycin is a proteoglycan secreted by gastric cancer cells. It binds to the CD44 receptor on regulatory T cells to promote their differentiation and maintain their suppressive functions, allowing the tumor to evade the immune system.

How does the serglycin-CD44 axis affect LAG3 expression?

This axis triggers metabolic changes, including increased glycolysis and ROS clearance. This environment prevents the oxidative modification of LAG3 at the M171 residue, which prevents its degradation and leads to increased LAG3 protein levels on Tregs.

Disclaimer: This content is for informational and educational purposes only and does not constitute medical advice. It is not intended to be a substitute for professional medical judgment, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Refer to the latest local and national guidelines for clinical practice.

References

Wang Q et al. Serglycin Drives LAG3+ Treg Differentiation and Immunosuppression in Gastric Cancer. Cancer Res. 2026 Feb 24. doi: 10.1158/0008-5472.CAN-25-3071. PMID: 41734377.

Li X, et al. The role of CD44 in the tumor immune microenvironment. J Hematol Oncol. 2023.

Zhang Y, et al. LAG3 as a target in cancer immunotherapy. Front Immunol. 2024.