Data from 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 do not benefit from treatment. Although previous studies have shown that hydrogen sulfide (H₂S) is involved in colorectal cancer 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 colorectal cancer 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–CTLA4 treatment. H₂S promoted Treg activation through the 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 colorectal cancer 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 colorectal cancer.

H₂S depletion increases the CD8⁺ T-cell/Treg ratio and enhances the efficacy of anti–PD-L1 and anti–CTLA4 treatment in colon cancer, identifying H₂S as an anticancer immunotherapy target.