BCG Vaccination Reprograms the Function of M‐MDSCs and Aggravates Necrotizing Enterocolitis in Neonates

ABSTRACT Bacillus Calmette–Guérin (BCG), a live‐attenuated vaccine primarily used against tuberculosis (TB), also provides protection against a broad array of antigens or heterologous antigens through the induction of trained immunity (TI). While BCG is generally safe for full‐term infants, its application in preterm infants is contentious due to their immature immune systems and heightened susceptibility to adverse effects. Preterm infants, particularly those with low birth weight, are at an elevated risk of severe complications, such as necrotizing enterocolitis (NEC), a life‐threatening inflammatory condition of the intestines. NEC is characterised by dysregulated immune responses to microbial colonisation, with myeloid‐derived suppressor cells (MDSCs) playing a crucial role in maintaining immune tolerance during early life. This study reveals that BCG vaccination significantly exacerbates NEC severity ( p = 0.0048) by enhancing glycolysis and upregulating mTOR‐HIF1α signalling in neonatal monocytic MDSCs (M‐MDSCs), thereby impairing their immunosuppressive function. Pharmacological or genetic inhibition of mTOR‐HIF1α signalling or glycolysis pathways restored M‐MDSC function and mitigated NEC severity. These findings complement our previous work on BCG's effects on polymorphonuclear (PMN)‐MDSCs and highlight the dual role of BCG: while it provides protective benefits in certain contexts, it may also increase NEC risk in preterm infants by disrupting MDSC‐mediated immune tolerance. This study offers critical insights into the mechanisms underlying BCG's off‐target effects and underscores the necessity of tailored vaccination strategies for preterm infants to minimise potential risks.