Intratumoral microbiota-derived S1P sensitizes the combination therapy of capecitabine and PD-1 inhibitors

Clinical responses of colorectal cancer (CRC) treatments vary considerably due to the heterogeneity of tumor microenvironment (TME), where intratumoral microbiota may reshape the unique inflammation imprints. However, its complex mechanistic underpinnings remain incompletely elucidated. Herein, we sought to delineate the critical role of intratumoral microbiota in potentiating combination therapeutics against CRC. By comparing germ-free (GF) and specific pathogen-free (SPF) mouse models of 33 potential CRC treatments, we screened out capecitabine-MIH4 (anti-PD-1 antibody) combination regimen significantly augmented by intratumoral microbiota in tumor regression. The enrichment of enterotoxigenic <i>Bacteroides fragilis</i> induced by Capecitabine-MIH4 was concomitant with elevated microbial sphingosine-1-phosphate, which further up-regulated tumoral PD-L1 expression by enhancing histone deacetylation at the <i>CD274</i> locus. This activation ultimately led to effector memory <i>CD8</i> ^<i>+</i> T cell expansion and exhausted T cell subset reduction within TME. To conclude, these findings highlight microbial sphingolipids as potential predictive biomarkers for strategies of targeting intratumoral microbiota in CRC management.