Cancers are well-known as complex diseases with high incidence and mortality rates.1 Recently, evolutionary biomedicine has offered a novel theoretical framework for understanding the emergence and progression of cancer.[2], [3] Cancer is considered a Darwinian evolutionary process within the body: individual tumor cells carrying advantageous survival mutations gain a competitive advantage through proliferation, gradually expanding and replacing less adaptive cells.4 From a macroevolutionary perspective, cancer is closely related to the evolution of multicellular life. The formation of multicellular organisms requires coordinated proliferation and differentiation among different cell types, a process that establishes complex molecular regulatory networks to maintain tissue homeostasis.5 However, many key genes that emerged during the origin of multicellular life are often located at pivotal positions connecting the single-cell and multicellular evolutionary regions. Once these genes undergo mutations or dysregulation, they can easily lead to cells escaping the constraints on proliferation imposed by multicellular organisms and undergoing carcinogenesis.6 Therefore the cancer ‘atavism’ theory proposes that cancer is a reactivation of ancient unicellular survival programs, representing a regression from multicellularity to a more primitive cellular state.7

The cancer ‘atavism’ theory provides a novel perspective for therapy and biomarker discovery of cancers. Under this framework, tumor cells abandon typical cooperative behavior in multicellular organisms, while expressing evolutionarily conserved genes to promote their own growth, survival, and adaptability.8 Previous studies have demonstrated that conserved genes, especially those originating from unicellular or early eukaryotic stages, are frequently upregulated in tumors, and their upregulated expression is associated with poor prognosis.[9], [10] Considering their essential role in core cellular functions, these genes might serve as robust biomarkers or drug targets across various cancer types.[3], [7], [10] Through dedifferentiation, tumor cells lose multiple functions acquired during multicellular evolution, and thus a novel therapeutic strategy is to implement interventions targeting these irreversibly lost functions, namely, to impose stresses on the tumor tissues that only fully cooperative multicellular systems can withstand.11 These evolutionary insights deepen our understanding of cancer biology and provide new perspectives for developing tailored therapy strategies.