Intratumoral microbiota-derived sphingolipids enhance the combination therapy of Capecitabine and Nivolumab

Intratumoral microbiota have exerted a profound impact on cancer treatments, however, its complex mechanistic underpinnings remain incompletely elucidated. Herein we sought to delineate the critical role of intratumoral microbiota in potentiating combination therapeutics against colorectal cancer (CRC). By conducting comparative analyses of germ-free (GF) and specific pathogen-free (SPF) mice models, we have screened out the intratumoral microbiota-augmented tumor regression and prolonged survival of SPF mice receiving Capecitabine-Nivolumab combination regimen. Its metagenomic and metabolomic profiling revealed an enrichment of Bacteroides fragilis by Capecitabine-Nivolumab combination therapy, concomitant with elevated microbial sphingosine-1-phosphate (S1P). Further mechanistic exploration demonstrated that intratumoral microbiota-derived S1P up-regulated PD-1 expression via epigenetic modulation—specifically, by enhancing histone deacetylation at the PDCD1 locus. Then we identified microbial sphingosine kinase 2 (SphK2) as a putative predictive biomarker for clinical benefit, underscoring the potential for intratumoral microbiota-targeted strategies to optimize CRC management. To conclude, these findings have advanced our understanding of the intricate interplay among intratumoral microbiota, sphingolipid metabolites and immunochemotherapeutic interventions, highlighting the promise of leveraging the intratumoral microbiome to enhance clinical outcomes in CRC.