Simple SummaryAlthough there is strong evidence linking oral microbiota to several types of cancer, the causal connections between them remain controversial. This study aims to identify the common oral bacteria associated with various types of cancer and detect potential mechanisms underlying the oral microbiota that could activate immune responses and lead to the onset of cancer through cytokine secretion. We have confirmed that alterations in the composition of oral bacteria can contribute to a reduction in SCFAs and the expression of the FFAR 2, resulting in an inflammatory response through the upregulation of TNFAIP8 and the IL-6/STAT3 pathway, ultimately increasing the risk of cancer onset. These findings provide valuable insights into the potential role of the oral microbiome in cancer development and could pave the way for novel preventive and therapeutic strategies for cancer.AbstractThe association between oral microbiota and cancer development has been a topic of intense research in recent years, with compelling evidence suggesting that the oral microbiome may play a significant role in cancer initiation and progression. However, the causal connections between the two remain a subject of debate, and the underlying mechanisms are not fully understood. In this case–control study, we aimed to identify common oral microbiota associated with several cancer types and investigate the potential mechanisms that may trigger immune responses and initiate cancer upon cytokine secretion. Saliva and blood samples were collected from 309 adult cancer patients and 745 healthy controls to analyze the oral microbiome and the mechanisms involved in cancer initiation. Machine learning techniques revealed that six bacterial genera were associated with cancer. The abundance ofLeuconostoc,Streptococcus,Abiotrophia, andPrevotellawas reduced in the cancer group, while abundance ofHaemophilusandNeisseriaenhanced. G protein-coupled receptor kinase, H+-transporting ATPase, and futalosine hydrolase were found significantly enriched in the cancer group. Total short-chain fatty acid (SCFAs) concentrations and free fatty acid receptor 2 (FFAR2) expression levels were greater in the control group when compared with the cancer group, while serum tumor necrosis factor alpha induced protein 8 (TNFAIP8), interleukin-6 (IL6), and signal transducer and activator of transcription 3 (STAT3) levels were higher in the cancer group when compared with the control group. These results suggested that the alterations in the composition of oral microbiota can contribute to a reduction in SCFAs and FFAR2 expression that may initiate an inflammatory response through the upregulation of TNFAIP8 and the IL-6/STAT3 pathway, which could ultimately increase the risk of cancer onset.