Serglycin Drives LAG3+ Treg Differentiation and Immunosuppression in Gastric Cancer

The enrichment of CD4+ regulatory T cells (Tregs) drives gastric cancer immunosuppression. Revealing the underlying mechanisms driving Treg differentiation could help develop strategies to stimulate anti-tumor immunity. Serglycin, derived from tumor cells, facilitates tumor progression in gastric cancer primarily via its receptor CD44, which is highly expressed in T cells, especially Tregs. This study investigated the immunomodulatory functions of tumor cell-derived serglycin in gastric cancer. Analysis of an integrated single-cell RNA-sequencing dataset of 23 paired gastric cancer tissues and adjacent normal gastric mucosa tissues revealed that Tregs were enriched in the gastric cancer tissues and associated with serglycin levels. Functionally, serglycin promoted differentiation of a specific subset of LAG3+ Tregs and maintained their suppressive function by activating the CD44/TGFβRI/Smad3 signaling pathway. Mechanistically, serglycin-CD44 signaling triggered glycolysis and facilitated ROS clearance, which attenuated the M171 oxidative modification of LAG3. Reduced oxidation led to enhanced LAG3 dimerization while disrupting the interaction with PELI1 to suppress K48-linked ubiquitination and degradation of LAG3, leading to LAG3 upregulation in Tregs. Blocking serglycin-CD44 signaling suppressed LAG3+ Treg differentiation and function, relieved immunosuppression, and inhibited tumor progression. Collectively, these findings identify a serglycin-CD44-mediated glycolysis-oxidation-ubiquitination cascade that functions as a critical driver of LAG3+ Treg differentiation in gastric cancer and provide pre-clinical evidence for targeting this axis to improve immunotherapeutic efficacy.