Identification and validation of a lactylation-related prognostic signature and the role of MELTF as a novel biomarker in lung adenocarcinoma

Abstract Background Lung adenocarcinoma (LUAD) is a major cause of cancer death. While treatments exist, we still lack reliable tools to predict which patients will do well or respond to specific therapies like immunotherapy. Tumor cells often produce large amounts of lactate, a metabolic byproduct. This lactate can drive a newly discovered chemical modification on proteins called lysine lactylation. The role of this lactylation process in LUAD progression and its interaction with the immune system remains poorly understood. Methods We combined data from single-cell RNA sequencing (scRNA-seq) and bulk transcriptomic studies. We used a computational tool ("copykat") to distinguish cancer cells from normal cells within the tumor samples. Based on genes known to be involved in lactylation, we developed a 16-gene signature to predict patient survival using data from the TCGA-LUAD cohort. We then tested this signature's accuracy in several other independent patient groups. We also examined how this signature related to the types of immune cells present in the tumor and predicted response to drugs. Finally, we performed lab experiments to test the function of MELTF , a key gene identified in our signature. Results Our 16-gene lactylation signature effectively divided LUAD patients into high- and low-risk groups, with significant differences in survival across all tested cohorts. Patients in the high-risk group had a more immunosuppressive tumor environment and were more likely to benefit from chemotherapy agents like cisplatin and etoposide. In contrast, patients in the low-risk group showed a better potential response to PD-L1 inhibitors. Laboratory tests confirmed that reducing MELTF levels slowed down lung cancer cell growth, linking it directly to tumor aggressiveness. Conclusions We have developed a robust prognostic signature based on lactylation-related genes that can stratify LUAD patients and predict their likely response to both chemotherapy and immunotherapy. Our findings highlight MELTF as a novel oncogene and a potential new target for treatment. This work provides a practical framework for advancing personalized medicine in lung adenocarcinoma.