Cancer SLC6A6-mediated taurine uptake transactivates immune checkpoint genes and induces exhaustion in CD8+ T cells.

Taurine is used to bolster immunity, but its effects on antitumor immunity are unclear. Here, we report that cancer-related taurine consumption causes T cell exhaustion and tumor progression. The taurine transporter SLC6A6 is correlated with aggressiveness and poor outcomes in multiple cancers. SLC6A6-mediated taurine uptake promotes the malignant behaviors of tumor cells but also increases the survival and effector function of CD8+ T cells. Tumor cells outcompete CD8+ T cells for taurine by overexpressing SLC6A6, which induces T cell death and malfunction, thereby fueling tumor progression. Mechanistically, taurine deficiency in CD8+ T cells increases ER stress, promoting ATF4 transcription in a PERK-JAK1-STAT3 signaling-dependent manner. Increased ATF4 transactivates multiple immune checkpoint genes and induces T cell exhaustion. In gastric cancer, we identify a chemotherapy-induced SP1-SLC6A6 regulatory axis. Our findings suggest that tumoral-SLC6A6-mediated taurine deficiency promotes immune evasion and that taurine supplementation reinvigorates exhausted CD8+ T cells and increases the efficacy of cancer therapies.

Blocked erythroid differentiation and delayed enucleation of erythroblasts may contribute to murine embryonic toxicity upon exposure to low dose of cadmium.

Epidemiological and experimental studies have demonstrated the association of spontaneous abortion or embryonic atrophy with heavy metals, including some well-known anemia inducers, such as cadmium (Cd). However, the direct adverse effect of Cd on embryos without inducing maternal anemia remains unclear. In this study, we treated mice with a low dose of Cd before and after mating to minimize Cd-induced maternal anemia. Although most embryos developed normally, embryonic atrophy was still observed in a small percentage of embryos from Cd-exposed pregnant mice. Compared to the embryos from the control pregnant mice, a complete blockage of erythroid differentiation was observed in the atrophic embryos but no obvious alteration of erythroid differentiation in the non-atrophic embryos, respectively. Moreover, our results suggested delayed enucleation of erythroblasts in these non-atrophic embryos. Mechanically, the inhibited iron transport from the placenta to the fetus together with the increased iron export in the fetal livers might contribute to embryonic atrophy and delayed enucleation of erythroblasts upon Cd exposure. Our data may provide new insights into the embryonic toxicity of low-dose Cd.

Important roles of heme-regulated eIF-2α kinase in cadmium-induced glycolysis under acute exposure.

Cadmium (Cd) is a well-known heavy metal pollutant that is a toxic threat to human health. Cadmium can induce anemia and is involved in metabolic disorders. Heme-regulated eIF2α kinase (HRI) is the main regulator of terminal erythropoiesis and is required to prevent anemia and toxicity in the liver and kidneys in response to various stresses including Cd exposure. However, the involvement of HRI in Cd-induced metabolic disorders remains unclear. In this study, we performed proteomics on plasma collected from wild-type and Hri knockout mice treated with or without 5 and 10 mg/kg Cd. In total, 382 proteins were identified and indicated that the number of proteins in wild-type (Wt) mice was 2.4-fold higher than that in Hri knockout mice after Cd exposure, indicating the requirement of HRI for Cd exposure responses. Proteins associated with glycolysis were the most upregulated after Cd exposure in Wt mice, while, the induction of glycolysis after Cd exposure was interrupted in Hri knockout mice, suggesting the involvement of HRI in Cd-induced glycolysis upon acute exposure. Our results will help identify potential targets involved in metabolic disorders following acute exposure to high doses of cadmium.

Lactate: a pearl dropped in the ocean-an overlooked signal molecule in physiology and pathology.

Lactate, once recognized as a wasty product from anaerobic glycolysis, is proved to be a pivotal signal molecule. Lactate accumulation occurs in diverse physiological and pathological settings due to the imbalance between lactate production and clearance. Under the condition with drastic changes in local microenvironment, such as tumorigenesis, inflammation, and microbial infection, the glycolysis turns to be active in surrounding cells leading to increased lactate release. Meanwhile, lactate can be utilized by these cells as an energy substrate and acts as a signal molecule to regulate cell functions through receptor-dependent or independent pathways. In this review, we tended to tease out the contribution of lactate in tumor progression and immunomodulation. And we also discussed the accessory role of lactate, beyond as the energy source only, in the growth of invading pathogens.