UBA5 inhibition restricts lung adenocarcinoma via blocking macrophage M2 polarization and cisplatin resistance.

UBA5, a ubiquitin-like activated enzyme involved in ufmylation and sumoylation, presents a viable target for pancreatic and breast cancer treatments, yet its role in lung adenocarcinoma (LUAD) remains underexplored. This study reveals UBA5's tumor-promoting effect in LUAD, as evidenced by its upregulation in patients and positive correlation with TNM stages. Elevated UBA5 levels predict poor outcomes for these patients. Pharmacological inhibition of UBA5 using DKM 2-93 significantly curtails the growth of A549, H1299, and cisplatin-resistant A549 (A549/DDP) LUAD cells in vitro. Additionally, UBA5 knockdown via shRNA lentivirus suppresses tumor growth both in vitro and in vivo. High UBA5 expression adversely alters the tumor immune microenvironment, affecting immunostimulators, MHC molecules, chemokines, receptors, and immune cell infiltration. Notably, UBA5 expression correlates positively with M2 macrophage infiltration, the predominant immune cells in LUAD. Co-culture experiments further demonstrate that UBA5 knockdown directly inhibits M2 macrophage polarization and lactate production in LUAD. Moreover, in vivo studies show reduced M2 macrophage infiltration following UBA5 knockdown. UBA5 expression is also associated with increased tumor heterogeneity, including tumor mutational burden, microsatellite instability, neoantigen presence, and homologous recombination deficiency. Experiments indicate that UBA5 overexpression promotes cisplatin resistance in vitro, whereas UBA5 inhibition enhances cisplatin sensitivity in both in vitro and in vivo settings. Overall, these findings suggest that targeting UBA5 inhibits LUAD by impeding cancer cell proliferation, M2 macrophage polarization, and cisplatin resistance.