TCF7 (transcription factor 7) is a critical transcriptional regulator that plays essential roles in T-cell differentiation and anti-tumor immunity. TCF7 functions as a key determinant of T-cell stemness and memory formation, with TCF7+ CD8+ T cells representing a stem-like, less exhausted population that is crucial for effective immune responses 1. In the context of cancer immunotherapy, TCF7 expression serves as a positive predictor of checkpoint blockade response, with TCF7+ T cells associated with improved clinical outcomes in melanoma patients 1. Mechanistically, TCF7 expression is regulated through epigenetic modifications, including H3K27 acetylation at its super-enhancer region, which can be modulated by microbial metabolites like indole-3-propionic acid to enhance immunotherapy efficacy 2. Additionally, TCF7 expression is preserved through O-GlcNAcylation of β-catenin following mannose metabolism enhancement, promoting stem-like programs in T cells and restricting exhaustion differentiation 3. The presence of TCF7+ naive and memory T cells is associated with tertiary lymphoid structures in tumors, which correlate with improved survival and immunotherapy response 4. These findings establish TCF7 as a critical transcriptional regulator that maintains T-cell stemness and enhances anti-tumor immunity across multiple cancer types.