NPRL2 promotes TRIM16-mediated ubiquitination degradation of Galectin-3 to prevent CD8⁺T lymphocyte cuproptosis in glioma

Our previous study found that tumor suppressor nitrogen permease regulator like-2(NPRL2) is frequently downregulated in glioma, leading to malignant growth. However, NPRL2-mediated crosstalk between tumor cells and immune cells remains unclear.

The regulatory effects of NPRL2 on tripartite motif–containing protein 16(TRIM16) dependent ubiquitination degradation of Galectin-3(Gal-3) were explored. The effects of Gal-3 on copper uptake, immunocompetence and cuproptosis were investigated in CD8⁺T lymphocytes(CD8⁺T cells). The ability of NPRL2 to protect CD8⁺T cells from Gal-3 damage was evaluated. Furthermore, the correlations among NPRL2, TRIM16, Gal-3 and CD8⁺T cell accumulation were analyzed in glioma clinical specimens.

NPRL2 increased the TRIM16 expression via inactivation of ERK1/2, which in turn promoted the ubiquitination-mediated degradation of Gal-3 and diminished Gal-3 release from glioma cells. Moreover, Gal-3 accelerated copper uptake and triggered cuproptosis in CD8⁺T cells, whereas NPRL2 increased CD8⁺T cell recruitment and prevented impairment of CD8⁺T cells by Gal-3. Clinical samples revealed that NPRL2 expression was positively associated with TRIM16 expression and negatively correlated with Gal-3, but Gal-3 expression was negatively associated with CD8⁺T cell accumulation.

Glioma-derived NPRL2/TRIM16/Gal-3 axis participates in the regulation of CD8⁺T cell cuproptosis, which provides a promising strategy to rescue the immune activity of CD8⁺T cells and reverse immunosuppression in glioma.