Hence, we analyzed major genes relevant for tumor-reactive CD8+ T cell exhaustion (TIGIT, PDCD1, LAG3, CTLA4, HAVCR2, ENTPD1, TCF7, TOX, EOMES, CXCL10, CXCL9, CXCL13, CXCR5, ICOS, IL18R1, IL15RA, IL18RAP, KLRG1, KLRK1, BCL6, SLAMF6)40 (Supplementary Table S3), and critical cytokine or TCR signaling related components as well as transcription factors (TFs) upstream of exhaustion-relevant IR-coding genes (IL2, CD28, TNF, SMAD3, SMAD4, SMAD2, NFATC1, NFATC3, NFATC2, MAF, STAT2, STAT1, JAK3, PRDM1, TBX21, YY1, NFIL3)36. This evidence concerns the gene SMAD3 and neoplasm.