The interplay of DNA damage, epigenetics and tumour heterogeneity in driving cancer cell fitness.

Intra-tumor heterogeneity is a primary cause of therapeutic failure, driving tumor progression. Within tumors, diverse cell states coexist, maintained by a specific chromatin landscape that influences various cell functions, including cancer stemness. Among factors that induce chromatin changes affecting cell state fitness, DNA damage and its repair have emerged as significant contributors. This perspective examines recent advances that elucidate the interplay between DNA repair, epigenome, and cell plasticity. We discuss how epigenome affects DNA repair and, conversely, how DNA repair-induced chromatin changes influence cell plasticity. Finally, we discuss emerging concepts and highlight the therapeutic implications of these interconnected mechanisms.