Siglec-G suppresses CD8+ T cells responses through metabolic rewiring and can be targeted to enhance tumor immunotherapy

CD8+ T cells play a critical role in cancer immune-surveillance and pathogens elimination. However, their effector function can be severely impaired due to inhibitory receptors such as PD-1 and Tim-3. Here we identify Siglec-G as a novel coinhibitory receptor that limits CD8+ T cell function. Siglec-G is highly expressed on tumor-infiltrating T cells and is enriched in the exhausted T cell subset. Ablation of Siglec-G enhances the efficacy of adoptively transferred T cells and CAR T cells to repress the growth of solid tumors. Mechanistically, sialic acids on tumor cells trigger Siglec-G-SHP2 axis in CD8+ T cells, and impairs metabolic reprogramming from OXPHOS to glycolysis, which dampens CTL activation, expansion and cytotoxicity. These findings define a critical role for Siglec-G in inhibiting CD8+ T cell responses, which strongly suggests its therapeutic effect in adoptive T cell therapy and tumor immunotherapy. To compare the difference between TILs and Teff, we isolated TILs from MC38-OVA-bearing mice and Teff from LM-OVA infected mice