Ultimately, the exhaustion state is the outcome of a transcriptional and metabolic reprogramming induced by immunosuppressive cytokines (i.e., TGF-β, IL-10) and metabolites (i.e., lactate, kynurenine, adenosine, PGE2) produced by cancer cells (121, 123) and tumor infiltrating immunosuppressive cell subsets, including regulatory T cells, myeloid-derived suppressor cells, tumor-associated macrophages, cancer-associated fibroblasts, adipocytes, and endothelial cells (124). This evidence concerns the gene TGFB1 and neoplasm.