Background <p>Immunocompromised hosts (ICHs) face elevated risks of severe respiratory infections and mortality. Glucocorticoids, commonly used to treat underlying conditions in ICHs, may further impair immune defenses, but the underlying mechanisms remain unclear.</p> Methods <p>Retrospective analysis of peripheral blood immune cell profiles was conducted in pneumonia patients with ICHs. Prospective immunophenotyping of PBMCs by Cytek flow cytometry was performed to compare immune cell subsets in survivors versus deceased patients. To explore glucocorticoid effects on ICH immune mechanisms, we used a murine model of severe pneumonia (MRL/lpr mice) and an in vitro ICH infection mimic model. Glucocorticoid effects on immune cell populations and function were examined in these models.</p> Results <p>Focusing on key immune cells, we observed that ICH patients with severe pneumonia exhibit a reduction in classical monocyte subsets. Mechanistically, glucocorticoids downregulated CCL2 expression in the lung via GR/STAT3, thereby inhibiting the PA-LPS/TLR4/PI3K/AKT/STAT signaling pathway and diminishing pulmonary CCL2 and Ly6C⁺CCR2⁺ monocyte levels. Importantly, exogenous recombinant CCL2 administration restored monocyte function, reduced lung injury, and enhanced survival.</p> Conclusion <p>These findings uncovered a critical immunosuppressive mechanism by which glucocorticoids, via GR/STAT3-mediated suppression of the CCL2-CCR2 axis, impair monocyte-driven antibacterial responses in severe pneumonia, highlighting the need for targeted immunomodulation in ICH patients.</p>