Lung cancer remains the second most prevalent malignancy worldwide and is characterized by persistently high incidence and mortality rates. As the disease progresses, most patients develop immune evasion and metastatic dissemination, which represent major threats to overall survival. The advent of targeted therapies and immunotherapies has fundamentally reshaped the clinical management of lung cancer; however, therapeutic resistance and limited durability of response remain critical challenges. Lactylation has recently emerged not only as a novel post-translational modification but also as a potential therapeutic vulnerability in lung cancer. By modulating the activity, stability, and transcriptional functions of both histone and non-histone proteins, lactylation reshapes tumor metabolism, immune evasion, and resistance-associated signaling pathways. Importantly, growing evidence suggests that therapeutic strategies targeting lactylation-related pathways may offer new opportunities to improve outcomes in patients with advanced lung cancer and overcome acquired resistance to existing therapies. In this review, we systematically delineate the molecular mechanisms underlying lactylation, with particular emphasis on the enzymatic machinery governing lactylation dynamics and its regulatory network. We synthesize current evidence describing how lactylation-driven signaling programs contribute to lung cancer progression, immune escape, and treatment resistance, highlighting the complex interplay between lactylation pathways and lung cancer pathobiology. Furthermore, we critically evaluate the translational potential of lactylation sites and their downstream effectors as diagnostic and prognostic biomarkers, as well as actionable therapeutic targets. Collectively, these findings support the concept that targeting lactylation-associated regulatory circuits represents an emerging and potentially more selective therapeutic strategy for lung cancer. Nevertheless, clinical translation remains constrained by the lack of specific intervention tools, standardized detection methodologies, and robust human data. Future studies should prioritize the development of precise lactylation-targeted approaches and large-scale, longitudinal clinical investigations to validate their clinical value and overcome current translational bottlenecks.
Li et al. (2026) studied this question.