<p>Anti-PD-1 therapy has significantly improved the clinical outcomes of patients with advanced lung adenocarcinoma (LUAD). However, primary and acquired drug resistance remain common and are largely driven by an immunosuppressive tumor microenvironment (TME). Lactate accumulation has emerged as a key metabolic determinant that shapes immunosuppressive niches. However, how lactate-derived epigenetic modifications regulate tumor immune escape and resistance to anti-PD-1 therapy in LUAD remains unclear. Here, we revealed that the KAT2A-IGF2BP1-CXCL2 axis in LUAD mediated recruiting myeloid-derived suppressor cells (MDSCs) and PD-1 blockade resistance. Clinically, pan-lactylation levels are significantly elevated in anti-PD-1-resistant LUAD samples and are correlated with high cell proliferation and elevated lactate levels in the tumor microenvironment. Single-cell transcriptomics revealed that KAT2A was enriched in epithelial cells and tumor-associated macrophages (TAMs) of therapy-resistant cases, where KAT2A was linked to immunosuppression. It has been further confirmed that KAT2A promoted lactylation of the N6-methyladenosine (m⁶A) reader IGF2BP1 at site K228 in vivo and in vitro experiments. This modification enhances IGF2BP1’s binding to the m⁶A site within CXCL2 mRNA, thereby increasing CXCL2 stability. KAT2A facilitated resistance to anti-PD-1 therapy in LUAD, inhibited the recruitment of CD8⁺ T cells, and significantly increased the infiltration of MDSCs. Furthermore, animal experiments demonstrated that targeted inhibition of KAT2A activity markedly enhanced the sensitivity of LUAD to anti-PD-1 therapy. This study provided a comprehensive exploration of KAT2A’s oncogenic functions. It suggests a novel strategy to enhance the efficacy of anti-PD-1 therapy by inhibiting the KAT2A-IGF2BP1-CXCL2 signaling axis in LUAD.</p>