Hydrogen sulfide creates a favorable immune microenvironment for colon cancer.

Immunotherapy can elicit robust anticancer responses in the clinic. However, a large proportion of patients with colorectal cancer (CRC) do not benefit from treatment. While previous studies have shown that hydrogen sulfide (H2S) is involved in CRC development and immune escape, further insights into the mechanisms and related molecules are needed to identify approaches to reverse the tumor supportive functions of H2S. Here, we observed significantly increased H2S levels in CRC tissues. Decreasing H2S levels by using CBS+/- mice or feeding mice a sulfur amino acid-restricted diet (SARD) led to a marked decrease in differentiated CD4+CD25+Foxp3+ Tregs and an increase in the CD8+ T cell/Treg ratio. Endogenous or exogenous H2S depletion enhanced the efficacy of anti-PD-L1 and anti-CTLA-4 treatment. H2S promoted Treg activation through persulfidation of ENO1 at cysteine 119. Furthermore, H2S inhibited the migration of CD8+ T cells by increasing the expression of AAK-1 via ELK4 persulfidation at cysteine 25. Overall, reducing H2S levels engenders a favorable immune microenvironment in CRC by decreasing the persulfidation of ENO1 in Tregs and ELK4 in CD8+ T cells. SARD represents a potential dietary approach to promote responses to immunotherapies in CRC.