Unveiling Lactylation: A Novel Frontier in Cancer Stemness and Therapy.

Cancer stemness represents a dynamic cellular state endowed with tumor-initiating capacity, self-renewal potential, and differentiation plasticity, functioning as a key driver of tumor recurrence, metastasis, and therapy resistance. Tumor metabolism and epigenetic regulation are two fundamental mechanisms that modulate cancer stemness. Lactylation, a novel post-translational modification, has emerged as a pivotal bridge linking these two processes. Accumulating evidence highlights elevated lactylation as a critical driver of cancer stemness. To elucidate the underlying mechanisms, we systematically evaluate how lactylation orchestrates the cancer stem cell (CSC) landscape across four functional dimensions: self-renewal maintenance, stemness-associated signaling activation, microenvironmental adaptation, and lineage plasticity induction. Furthermore, we summarize the dynamic regulatory network governing this modification, comprising both key enzymes and indirect modulators. Beyond highlighting promising therapeutic targets and preclinical successes, we critically assess the significant challenges hindering clinical translation. This framework provides a roadmap for targeting the metabolic-epigenetic circuitry of CSCs to combat therapy resistance and metastasis.