Dietary sulfur amino acids enhance anti-tumor immunity in colon cancer via an NKT cell-XCL1-cDC1 circuit.

The efficacy of immune checkpoint inhibitors (ICIs) in colon cancer (CC) is limited by the tolerogenic immune landscape of both the tumor and the intestine. Here, we investigated the impact of microbial metabolic pathways associated with ICI responsiveness on anti-tumor immunity in CC. Sulfur amino acid (Saa) metabolic pathways were enriched in ICI responders and in individuals without CC. In murine models, high-Saa diets restricted CC progression, increased colonic mucus thickness, and promoted the expansion of mucus-dwelling Mucispirillum schaedleri (M. schaedleri). Dietary Saa supplementation increased the frequency of activated intratumoral cytotoxic CD8+ T cells. The protective effect of high-Saa diets required type 1 conventional dendritic cells (cDC1s) in tumor-draining lymph nodes, where M. schaedleri was sufficient to drive cDC1 expansion and activation. Mechanistically, M. schaedleri stimulated natural killer T (NKT) cell expansion and secretion of the chemokine XCL1, which was essential for cDC1 recruitment and anti-tumor immunity. Dietary modulation of this NKT-XCL1-cDC1 axis in combination with ICIs may open avenues for improved treatments of CC.