Regulatory role of protein lactylation in tumor metastasis: mechanisms and emerging therapeutic strategies.
BACKGROUND Tumor metastasis is the primary cause of cancer-related mortality. This complex process is orchestrated by the tumor microenvironment (TME) and metabolic reprogramming. Protein lactylation, a newly recognized post-translational modification derived from lactate metabolism, is emerging as a critical regulator of tumor progression and metastasis. AIM OF REVIEW This review aims to provide an overview of the current understanding of lactylation within the metastatic process and to offer an updated perspective on its regulatory role in tumor metastasis and its promise as a new therapeutic avenue. KEY SCIENTIFIC CONCEPTS OF REVIEW The review focuses on both the enzymatic and non-enzymatic mechanisms of lactylation and delineates the enzymatic machinery, including writers, erasers, and readers, that dynamically regulate this modification. It emphasizes how lactylation influences critical stages of metastasis, such as the epithelial-mesenchymal transition (EMT) and invasion, cancer stemness maintenance, immune evasion and TME remodeling, angiogenesis and vascular dissemination, and survival during colonization. Beyond these stage-specific roles, this review discusses how lactylation operates within a broader post-translational modification (PTM) network through crosstalk with acetylation, ubiquitination, and RNA methylation to amplify oncogenic signaling. Finally, the review evaluates emerging therapeutic strategies targeting lactate metabolism, the lactylation machinery, and site‑specific modifications, and addresses persistent challenges including context‑dependent functions, limited causal validation, and technical hurdles in isomer‑specific detection.