ICI therapy blocks the engagement of PD‐L1 with its co‐inhibitory receptor PD‐1, reactivating and expanding tumor‐reactive CTLs.[41] Instead, pyroptosis‐enhanced CTL activation exerted a synergistic effect by promoting tumor cell sensitivity to ICI therapy.[42] However, the efficacy of ICI therapy in solid tumors such as CRC is lower than expected, and is even lower in MSS tumors.[43] Therefore, we explored whether YY2‐mediated CTL activation favored MSI and MSS CRCs sensitivity to ICI immunotherapy (Figure 7A; Figure S11A, Supporting Information). This evidence concerns the gene YY2 and Marinesco-Sjogren syndrome.