Thus, ncRNAs, especially the circulating ones that directly and indirectly target immune checkpoint molecules such as PD-1/PD-L1, TIM3, CTLA-4, B7-H3, and LAG-3, can be also implicated as biomarkers with great potential.125–127 There is a correlation between high TMB and response to ICIs in microsatellite instability high metastatic CRC.128 High TMB represents a high abundance of neo-epitopes that arise from the modification of proteins encoded by mutated genes, which leads to the activation of anti-cancer immune responses against those neoantigens. This evidence concerns the gene CTLA4 and cancer.