Beyond fueling tumor growth, lactate-derived lysine lactylation (Kla) has emerged as a pivotal epigenetic and post-translational modifier, directly coupling metabolic activity to the regulation of immune cell function and tumor cell resilience.<h4>Main body</h4>This review synthesizes current evidence to delineate how the glycolysis-lactylation axis orchestrates a multi-faceted immunosuppressive program and confers broad therapy resistance. The gene discussed is KL; the disease is neoplasm.