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Through integrated multi-omics analysis of 61 patient-derived fungal balls, we reveal their complex ecology. While\n                      <jats:italic toggle=\"yes\">Aspergillus fumigatus<\/jats:italic>\n                      dominates the fungal niche (59% of patients), bacterial co-colonization is ubiquitous, primarily by\n                      <jats:italic toggle=\"yes\">Pseudomonas aeruginosa<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">Haemophilus influenzae<\/jats:italic>\n                      . Metabolomics and metatranscriptomics unveil a structured division of labor and active warfare, including metabolic cross-feeding, competition for iron, and reciprocal antagonism via secondary metabolites, such as fumagillin and fumigaclavine C produced by\n                      <jats:italic toggle=\"yes\">A. fumigatus<\/jats:italic>\n                      . Host metabolomics and transcriptomics revealed a potent but dysregulated human immune response, characterized by neutrophil activation and failed resolution. Our findings redefine aspergilloma not as a mere fungal aggregate, but as a resilient polymicrobial biofilm across kingdoms, in which synergistic and antagonistic inter-kingdom interactions drive pathogenesis and chronicity, suggesting new therapeutic strategies targeting the pathogenic consortium.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        Chronic pulmonary aspergillosis (CPA) and its hallmark fungal balls (aspergillomas) represent a debilitating and difficult-to-treat respiratory disease, affecting millions worldwide. Here, we provide the first integrated multi-omics profile of surgically resected fungal balls from 61 CPA patients, revealing these structures not as mere fungal colonies, but as resilient, cross-kingdom biofilms teeming with bacterial co-colonizers, particularly\n                        <jats:italic toggle=\"yes\">Pseudomonas aeruginosa<\/jats:italic>\n                        and\n                        <jats:italic toggle=\"yes\">Haemophilus influenzae<\/jats:italic>\n                        . Our findings uncover a dynamic battlefield where fungi and bacteria engage in metabolic cross-feeding, chemical warfare, and competition for nutrients such as iron. We demonstrate that the host mounts a potent but dysregulated immune response characterized by chronic neutrophilic inflammation and failed resolution, driving tissue damage and disease persistence. Our data provide a foundation for novel therapeutic strategies aimed at disrupting microbial synergy, modulating host inflammation, and breaking the cycle of chronic infection, an approach that could significantly improve outcomes for patients with this refractory disease.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/mbio.00348-26","type":"journal-article","created":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T13:05:21Z","timestamp":1777986321000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":3,"title":["Multi-omics profiling of fungal balls in chronic pulmonary aspergillosis patients reveals microbiome dynamics and metabolic 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