LCL-161

The dynamic immune landscape within the tuberculous (TB) granuloma microenvironment critically governs antibiotic penetration efficiency, bacterial persistence, and long-term therapeutic outcomes. Herein, we present a macrophage-targeted inhalable nanoemulsion for co-delivering rifampicin and LCL161, an inhibitor of apoptosis protein antagonist. Inhaled mannose-nanoemulsions (named RL-NE@Man) enable granuloma-targeted delivery in TB mice model, increasing infected macrophage apoptosis, remodeling the tuberculosis microenvironment, and promoting T-cell immunity to synergize with antibiotics for the eradication of granulomas and persistent Mycobacterium tuberculosis infection. Following two-dose inhalational administration, RL-NE@Man displayed potent bactericidal activity against M. tuberculosis while concurrently alleviating pulmonary pathological lesions and hyperinflammatory responses, demonstrating superior bacterial suppression efficacy compared with that of the first-line rifampicin monotherapy. This inhaled combination therapy, which integrates immunomodulators with antibiotics to modulate the local immune landscape and synergistically enhance bactericidal efficacy, represents a novel therapeutic strategy for precision tuberculosis management.

Lung adenocarcinoma (LUAD) is associated with a poor prognosis. Manganese metabolism plays a critical role in antitumor immunity. The prognostic significance of manganese metabolism–related genes (MRGs) in LUAD remains unclear.

Single‐cell RNA sequencing and TCGA transcriptomic data were integrated to identify expressed MRGs. Cell subpopulations were defined using AUCell scoring. A prognostic signature was constructed using univariate Cox regression, LASSO regression and multivariate Cox analysis. A nomogram incorporating the manganese metabolism–related risk score (MRS) and clinical variables was developed, and predictive performance was evaluated using receiver operating characteristic curves. Immune infiltration patterns and drug sensitivity were further analysed.

A robust prognostic model based on nine genes, including KLRF1, demonstrated strong predictive performance. Patients in the high‐MRS group exhibited increased M1 macrophage infiltration and shorter overall survival, whereas the low‐MRS group was characterised by enrichment of resting dendritic cells. Drug sensitivity analyses suggested that JQ1 and Vorinostat may be more effective in low‐MRS patients, while Pevonedistat and LCL161 may be preferable for high‐MRS patients. In vitro experiments confirmed that high PTMA expression promoted malignant phenotypes in LUAD cells, and that combined JQ1 treatment and PTMA knockdown exerted synergistic antitumor effects.

We established and validated a prognostic signature based on nine MRGs. The synergistic antitumor effects of JQ1 and PTMA suppression were verified. This model provides a novel biomarker framework and therapeutic guidance for prognostic assessment and personalised treatment in LUAD.