Intestinal low-abundant bacteria drive MyD88/Trif-dependent CD8+ T cell exhaustion in chronic myeloid leukemia.

Leukemia stem cells (LSCs) resist therapy and immune elimination, but the basis of their escape from cytotoxic T cell (CTL) attack is unclear. Here, we show that specific low-abundance gut commensals of the genera Sutterella and Bilophila suppress anti-leukemic immunity in chronic myeloid leukemia (CML). Germ-free and specific opportunistic pathogen-free mice were protected from CML progression, whereas colonization with Sutterella strains-but not other bacteria-restored disease. In specific pathogen-free CML mice, higher Sutterella prevalence correlated with MyD88/Trif-dependent CTL exhaustion, marked by upregulation of exhaustion markers, reduced interferon-γ and granzyme B production, impaired ex vivo LSC killing, and transcriptomic signatures of exhaustion. These results establish a direct link between the gut microbiota and immune regulation of LSCs, identifying Sutterella species as critical modulators of CTL dysfunction and CML progression. This work highlights microbial influences on cancer immunity and suggests potential therapeutic avenues.