Sphingomonas -driven sphingosine signalling enhances neoadjuvant therapy responses in digestive system cancers

Neoadjuvant therapy (NAT) is becoming an essential component in the management of digestive system malignancies, yet whether the microbiome modulates NAT efficacy remains unclear. Here, we profile the intratumoral microbiome of patients with digestive system cancers following NAT and identify Sphingomonas as markedly enriched in pancreatic ductal adenocarcinoma (PDAC) tumors from responders. Sphingomonas was likewise detected in gastric and colorectal cancers with favourable NAT responses. Using mouse models, we show that Sphingomonas stably colonizes pancreatic, gastric, and colorectal tumors and augments NAT efficacy through secretion of sphingosine. Mechanistically, Sphingomonas -derived sphingosine binds lipid raft structures on the plasma membrane and is preferentially internalized by immune cells, where it selectively activates the ceramide-sphingomyelin synthetic pathway rather than the Sphingosine-1-Phosphate (S1P) pathway. This process amplifies lipid raft organization, promotes immune synapse formation, and enhances immune-mediated tumor cell killing. We further develop a lipid-raft-targeted sphingosine delivery system that boosts immune activation and sensitizes tumors to NAT. Together, these findings uncover a previously unrecognized microbial determinant of NAT responsiveness in digestive system cancers and provide a conceptual and translational framework for microbiome-based patient stratification and therapeutic sensitization.