<p>Non‑small cell lung cancer (NSCLC), particularly lung adenocarcinoma (LUAD), exhibits a high rate of primary resistance to immune checkpoint inhibitors, underscoring the need to decipher the molecular mechanisms of immune evasion. Here, we identify ANKRD49 as a critical regulator of PD‑L1 expression and immunosuppression in LUAD. Immunohistochemical analysis of clinical LUAD specimens revealed that high ANKRD49 expression correlates with reduced CD4⁺ and CD8⁺ T cell infiltration, increased FOXP3⁺ regulatory T cells, and elevated PD‑L1 levels. Functional experiments demonstrated that ANKRD49 overexpression in LUAD cells suppresses T cell cytotoxicity, promotes T cell apoptosis, and impairs granzyme B and IFN‑γ production in vitro. Mechanistically, ANKRD49 directly binds the transcription factor MEF2A via its second ankyrin repeat domain, upregulates MEF2A expression, and promotes its transcriptional activity at two specific sites within the PD‑L1 promoter. Chromatin immunoprecipitation and luciferase reporter assays confirmed that MEF2A directly activates PD‑L1 transcription in an ANKRD49‑dependent manner. In subcutaneous and metastatic mouse models, ANKRD49 overexpression accelerates tumor growth and metastasis, while PD‑L1 blockade reverses these effects and restores antitumor immunity. Collectively, our findings establish the ANKRD49–MEF2A–PD‑L1 axis as a novel driver of immune evasion in LUAD, and identify ANKRD49 ankyrin repeat domain 2 as a potential therapeutic target for overcoming immunotherapy resistance.</p>