Irradiation‐induced polyploid giant cancer cells are involved in tumor cell repopulation via neosis

Tumor repopulation occurs when residual tumor cells surviving therapies tenaciously proliferate and re‐establish the tumor. The cellular and molecular mechanisms underlying this process remain poorly understood. In this study, we propose that polyploid giant cancer cells (PGCCs) are involved in tumor repopulation via neosis following radiotherapy. We found that although the majority of PGCCs induced by irradiation underwent cell death, some PGCCs exhibited proliferative capacity. Utilizing time‐lapse microscopy and single‐cell cloning assays, we observed that proliferating PGCCs underwent neosis, thereby contributing to tumor cell repopulation after irradiation. Notably, HMGB1 released from dying tumor cells rather than intracellular HMGB1 could promote neosis‐based tumor repopulation, and the latter could be suppressed by the use of HMGB1 inhibitors. Taken together, our results indicate that PGCC can initiate tumor repopulation via neosis following radiation therapy.