TOX and neoplasm: Notably, a recent study uncovered that osteopontin (OPN) (encoded by SPP1) would activate CD29 on tumor-reactive CD8+ T cells and result in TOX-mediated CD8+ T cells dysfunction.28 Accordingly, SPP1 was significantly downregulated in IL-21R-TCR-T, which may contribute to the lower dysfunctional T cell subsets proportion in IL-21R-TCR-T (Supplementary Fig. 8d).