article · Redox Biology
Hydrogen sulfide is a gasotransmitter involved in cancer growth and immune regulation. This study examined the enzyme 3-mercaptopyruvate sulfurtransferase, or 3-MST, which produces hydrogen sulfide and polysulfides. In human renal cell carcinoma, 3-MST was found to be the most abundantly expressed enzyme generating hydrogen sulfide, with higher levels linked to lower patient survival. Pharmacological inhibition of 3-MST in renal cancer cells reduced hydrogen sulfide levels, halted cell proliferation, triggered cell death, and boosted the display of immunogenic markers including CD70, CD86, and PD-L1. Furthermore, partial enzyme inhibition stimulated T-cell activation in both helper and cytotoxic T cells. Functionally, inhibiting 3-MST enhanced the ability of cytotoxic T cells to destroy tumor cells, a response strengthened when paired with PD-L1 blockade. These findings identify 3-MST as a driver of tumor evasion and growth in kidney cancer.
Kidney cancer often resists treatment by hiding from the body's immune system. By pinpointing an enzyme that cancer cells rely on to produce hydrogen sulfide and suppress immune activity, this research reveals a metabolic target. Suppressing this enzyme can make tumors more visible and susceptible to immune attack, potentially improving patient outcomes when paired with existing immunotherapies.
This research highlights 3-MST as a potential therapeutic drug target for combination cancer immunotherapies, particularly alongside PD-L1 inhibitors for treating renal cell carcinoma. The target audience includes biopharmaceutical firms and drug discovery researchers developing metabolic or immune oncology therapies. Based on the cell-line assays and pharmacological experiments reported, the findings represent early-stage research that requires further preclinical validation before clinical translation can occur.
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Abstract Hydrogen sulfide (H₂S) is a redox-active gasotransmitter implicated in tumor progression and immune regulation. The enzyme 3-mercaptopyruvate sulfurtransferase (3-MST) is a key contributor to endogenous H₂S and polysulfide production, but its role in tumor–immune interactions remains poorly defined. Here, we show that 3-MST is the most abundantly expressed H₂S-synthesizing enzyme in human renal cell carcinoma cells (RCC) and that high 3-MST expression correlates with reduced patient survival. Pharmacological inhibition of 3-MST lowered intracellular H₂S levels in Renca renal carcinoma cells, suppressed proliferation, induced apoptosis, and increased surface expression of the immunogenic markers CD70, CD86, and PD-L1. In immune cells, partial inhibition of 3-MST promoted T cell activation, as evidenced by increased CD69 expression on both CD4⁺ helper and CD8⁺ cytotoxic T cells. In contrast, complete inhibition of 3-MST, achieved by high concentrations of the inhibitor, modestly reduced CD8⁺ T cell proliferation. Functionally, 3-MST inhibition potentiated antigen-specific CD8⁺ T cell-mediated killing of tumor cells, an effect further amplified by PD-L1 blockade. These results establish 3-MST as a redox-sensitive metabolic driver of tumor growth and immune evasion in RCC and demonstrate that its inhibition can boost antitumor immune responses, offering a potential avenue for combination immunotherapy.
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DOI: 10.1016/j.redox.2026.104373
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