Bacterial Elements Detected in Brain Tumors May Shape Tumor Microenvironment

The role of intratumoral microorganisms in cancer development, progression, and therapeutic response are active areas of research, but whether a diverse microbiome exists within and impacts the tumor microenvironment (TME) of the brain is an open question. Given preliminary evidence that bacteria may infiltrate the brain TME, Morad and colleagues performed a prospective, multi-institutional clinical study of 221 patients and analyzed samples representing gliomas, brain metastasis, tumor-adjacent normal tissue, and non-cancerous brain tissue. These samples were assessed via a robust workflow designed specifically for bacterial signal detection, characterization, and functional analysis. Bacterial 16S rRNA signals were detectable in primary and metastatic brain tumors and appeared to display patterns consistent with intracellular and extracellular localization. These microbial signals, assessed by both 16S rRNA detection as well as lipopolysaccharide staining, were found in most tumor samples tested but were notably absent in non-tumor controls. Spatial molecular imaging analysis further suggested that bacterial signals were present in tumor cells as well as various tumor-infiltrating immune and stromal cells. Although 16S rRNA signals were identified in freshly resected samples, standard culture techniques did not yield cultivable microbiota in tumor nor non-tumor samples. However, highly stringent bioinformatic analysis of intratumoral 16S signal from prospective patient cohorts underscored the finding that bacterial signals were present within tumor samples (46.6%, 55/118 positive) and largely missing from non-tumor samples (76.9%, 10/13 negative). Thirty-four bacterial taxa were observed, with some representing known human commensal bacterial strains as well as some environmental contaminants, as expected with the technical challenges of measuring low-abundance samples. Deep metagenomic shotgun sequencing and spatial molecular imaging further supported these observations. As evidenced through digital spatial profiling analysis, tumor regions of high 16S signals had higher enrichment of antimicrobial signatures, with both primary gliomas and brain metastases exhibiting expression programs consistent with Toll-like receptor pathway activation. Moreover, intratumoral bacterial sequences largely overlapped with the oral microbiota and to a lesser extent the gut microbiota, suggesting potential shared microbial reservoirs. Together, this study of clinical samples provides evidence for bacterial signals within the brain tumor microenvironment and proposes that further mechanistic study of the functional role and clinical impact of these signals is warranted.Morad G, Damania AV, Melendez B, Singh BB, Veguilla FJ, Soto RA, et al. Microbial signals in primary and metastatic brain tumors. Nat Med 2025;31:3675–88.Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at https://aacrjournals.org/cdnews.