Altered abundance in cancer patients gut of diadenylate cyclase-encoding bacteria

c-di-AMP is a bacterial second messenger recognized by host immune sensors such as the STING pathway, linking gut microbiota activity to tumor immunity. This interaction holds significant therapeutic potential particularly for oncologic patients, given the increasingly recognized relationship between gut microbiota and tumor immunity. Recent evidence shows that microbial c-di-AMP can enhance anti-tumor responses and improve the efficacy of PD-1/PD-L1 blockade and radiotherapy. This study identified gut microbial species capable of synthesizing c-di-AMP by mining the Unified Human Gastrointestinal Protein catalogue for diadenylate cyclases (DACs), generating a database of 4,228 DACs across 3,901 species out of 4,744 presents in the Unified Human Gastrointestinal Genome catalogue. Analysis of metagenomic data from 190 healthy subjects and 569 cancer patients (melanoma, NSCLC, renal carcinoma) revealed a significantly higher abundance of DAC-encoding species in healthy microbiota, with no differences between responders and non-responders to immunotherapy. These findings indicate that c-di-AMP-producing bacteria are depleted in cancer-associated microbiota, supporting further studies on their role in modulating anti-tumor immunity.