Protein Lactylation in Cancer: From Mechanisms to Therapy

ABSTRACT Protein lactylation has emerged as a metabolically responsive posttranslational modification linking lactate accumulation to epigenetic and functional adaptation in cancer. Initially identified on histones, lactylation is now recognized on diverse nonhistone proteins involved in DNA damage repair, immune regulation, redox homeostasis, metabolic remodeling, and cellular plasticity. However, current evidence remains fragmented across treatment modalities, and many reported lactylation events lack site‐specific functional validation and translational assessment. This review addresses this gap by integrating the metabolic and enzymatic basis of protein lactylation with its roles in chemotherapy, radiotherapy, targeted therapy, and immunotherapy. We critically examine how lactylation may promote tumor persistence under therapeutic pressure by enhancing genome maintenance, immune evasion, stress‐survival signaling, metabolic adaptability, and tumor microenvironment remodeling. We also evaluate emerging strategies targeting lactate production and transport, lactylation‐regulating enzymes, and functionally validated substrates, including their potential use in combination therapies. Finally, we discuss major barriers to clinical translation, including incomplete characterization of regulatory enzymes, limitations in site‐specific lactylome mapping, insufficient causal validation, lack of clinically qualified biomarkers, tumor metabolic heterogeneity, and challenges in achieving therapeutic selectivity. Collectively, protein lactylation represents an emerging mechanistic framework for understanding cancer treatment adaptation and a potentially targetable axis whose clinical relevance requires rigorous validation.