Targeted regeneration of post-radiation epithelium without promoting cancer recurrence

Cancer radiotherapy inevitably damages normal tissues, yet therapeutic activation of pro-survival or regenerative pathways frequently increases the risk of cancer recurrence. Strategies that selectively restore normal tissue without fueling malignant regrowth remain largely undefined. Using the slow dividing yet radio-responsive salivary gland and adjacent oral squamous cell carcinoma (OSCC) as paired in vivo models, we established a high-throughput genetic screening platform to quantify post-irradiation clonal expansion in both normal and malignant epithelium. Comparative screening revealed depletion of the salivary gland dominant SWI/SNF core ATPase Smarca2 as the top-ranking selective driver of salivary epithelial regeneration, in contrast to most candidates that promoted expansion in both tissues. Smarca2 depletion specifically enhanced regeneration of acinar cells, the lineage most refractory to recovery after irradiation, by suppressing terminal differentiation programs and enabling transcriptional activation of key regenerative genes. In OSCC cells, however, this regenerative switch was uncoupled from Smarca2 depletion due to tumor-specific chromatin state remodeling. Notably, this mechanism is conserved in human salivary gland tissue and can be induced using SMARCA2-targeting PROTAC degrader, a therapeutic class under active development for cancer treatment. Together, our findings suggest that Smarca2 depletion is a potent lineage-specific mechanism to replenish radiation damaged salivary epithelium without promoting OSCC expansion, a paradigm that is underexplored.