This study reveals that YY2 high expression‐mediated chromosome missegregation/micronuclei formation triggers pyroptosis and CTL activation by activating AIM2/caspase‐1/GSDMD cytosolic dsDNA response, and YY2/anti‐PD‐L1 combinatorial anti‐tumor therapeutic strategy. The gene discussed is YY2; the disease is neoplasm.