H₂S-Prdx4 axis mitigates Golgi stress to bolster tumor-reactive T cell immunotherapeutic response

The role of tumor microenvironment (TME)-associated inadequate protein modification and trafficking due to insufficiency in Golgi function, leading to Golgi stress, in the regulation of T cell function is largely unknown. Here, we show that disruption of Golgi architecture under TME stress, identified by the decreased expression of GM130, was reverted upon treatment with hydrogen sulfide (H₂S) donor GYY4137 or overexpressing cystathionine β-synthase (CBS), an enzyme involved in the biosynthesis of endogenous H₂S, which also promoted stemness, antioxidant capacity, and increased protein translation, mediated in part by endoplasmic reticulum-Golgi shuttling of Peroxiredoxin-4. In in vivo models of melanoma and lymphoma, antitumor T cells conditioned ex vivo with exogenous H₂S or overexpressing CBS demonstrated superior tumor control upon adoptive transfer. Further, T cells with high Golgi content exhibited unique metabolic and glycation signatures with enhanced antitumor capacity. These data suggest that strategies to mitigate Golgi network stress or using Golgi^hi tumor-reactive T cells can improve tumor control upon adoptive transfer.