Fares Darawshy (1,2,3); Jun-Chieh J. Tsay (1,4,5); Elizabeth Sanchez (1,4); Dong-Min Jin (6 3); Yeji Kim (7); Qingsheng Li (1,4); Matthew Chung (8); Anton Becker (9); Imran Sulaiman (1,10,11 4); Clea Barnett (1,4); Benjamin G. Wu (1,4,5); Ray Pillai (1,4); Benjamin Kwok (1,4); Kendrew Wong (1,4 5); Matthias C. Kugler (1,4); Yonghua Li (1,4); Rosemary Schluger (1,4); Destiny Collazo (1,4 6); Yaa Kyeremateng (1,4); Alexander Bain (1,4); Miao Chang (1,4); Jamie Bessich (1); Anrew DeMaio (1 7); Isaac Laniado (1); Daniel O’Neill (12); John J. Hall (13); Jonathan Sanders (13); George Thurston (4,7 8); Marcus D. Goncalves (4,14); Ezequiel Dantas (4); Rami Vanguri (15); Kwok Kin Wong (16,9); Daniel H. Sterman (1,4); Aristotelis Tsirigos (15); James T. Morton (13); Huilin Li (7); Elodie Ghedin (8 10); Leopoldo N. Segal (1,4,17).

Cancer immunotherapy research

To investigate the contribution of the lower airway microbiome to ICB responsiveness, Darawshy et al. analyzed BAL samples from 71 NSCLC patients prior to ICB treatment and compared functional microbial and host signatures between responders and non-responders. Multi-omic analyses of BAL revealed that enriched oral commensals correlated with poor ICB response, NSCLC progression, and worse prognosis, as well as upregulation of host interferon signaling, neutrophil degranulation and mitophagy. In a lung tumor model, inoculating oral commensals increased intratumoral neutrophils and Th17 responses, and impaired ICB efficacy.

Contributed by Katherine Turner

ABSTRACT: Immune checkpoint inhibitors (ICIs) have transformed the treatment of advanced non-small cell lung cancer (NSCLC), yet a large proportion of patients do not respond. The lung microbiome is a key modulator of antitumor immunity, however, the functional contribution of active microbial communities and their interaction with host transcriptional programs in shaping ICI outcomes remain poorly defined. Here, we prospectively analyzed bronchoalveolar lavage (BAL) samples from 71 NSCLC patients prior to ICI initiation. We profiled the microbiome and host transcriptome in the BAL to identify microbial and host signatures in the lower airways associated with treatment response. Our data indicate that enrichment of the lower airway microbiome with oral commensals was commonly associated with disease progression and worse prognosis of patients treated with ICI. Metatranscriptomics-derived microbial clustering revealed distinct functional profiles. The microbial cluster enriched with oral commensals, which was only present among patients with poor response to ICI, had differential regulation of pathways involved in the metabolism of short- chain fatty acid, methane and pyruvate. This cluster also correlated with host immune pathways including upregulation of interferon signaling, neutrophil degranulation, and mitophagy which could contribute to the poor response to immunotherapy. A preclinical murine model of lung cancer with dysbiosis was used to examine the nature of the association further. Inoculating lung tumor-bearing mice with oral commensals increased intratumoral neutrophils and Th17 responses and impaired ICI efficacy. Our findings support the concept that microbial communities in the lower airways appear to influence tumor–immune interactions via defined metabolic– immune axes.

Citation: Cancer immunotherapy research 2026