Cystine deprivation triggers CD36-mediated ferroptosis and dysfunction of tumor infiltrating CD8+ T cells.

Cancer cells develop multiple strategies to evade T cell-mediated killing. On one hand, cancer cells may preferentially rely on certain amino acids for rapid growth and metastasis. On the other hand, sufficient nutrient availability and uptake are necessary for mounting an effective T cell anti-tumor response in the tumor microenvironment (TME). Here we demonstrate that tumor cells outcompete T cells for cystine uptake due to high Slc7a11 expression. This competition induces T-cell exhaustion and ferroptosis, characterized by diminished memory formation and cytokine secretion, increased PD-1 and TIM-3 expression, as well as intracellular oxidative stress and lipid-peroxide accumulation. Importantly, either Slc7a11 deletion in tumor cells or intratumoral cystine supplementation improves T cell anti-tumor immunity. Mechanistically, cystine deprivation in T cells disrupts glutathione synthesis, but promotes CD36 mediated lipid uptake due to dysregulated cystine/glutamate exchange. Moreover, enforced expression of glutamate-cysteine ligase catalytic subunit (Gclc) promotes glutathione synthesis and prevents CD36 upregulation, thus boosting T cell anti-tumor immunity. Our findings reveal cystine as an intracellular metabolic checkpoint that orchestrates T-cell survival and differentiation, and highlight Gclc as a potential therapeutic target for enhancing T cell anti-tumor function.

Circulating Cell-Free mtDNA Content as a Non-invasive Prognostic Biomarker in HCC Patients Receiving TACE and Traditional Chinese Medicine.

Hepatocellular carcinoma (HCC) accounts for 70-85% of liver cancer, and about 85% of HCC are hepatitis B virus-related (HBV-HCC) in China. Transarterial chemoembolization (TACE) combined with traditional Chinese medicine (TCM) has been reported as an effective treatment. Potential biomarkers to stratify patients who may benefit from this treatment are needed. In this study, we aimed to evaluate whether circulating cell-free mitochondrial DNA (ccf-mtDNA) content was associated with the outcome of HCC patients, especially of those who received the combination treatment of TACE and TCM. Univariate and multivariate Cox analyses were conducted to evaluate the association between ccf-mtDNA content and the overall survival of HBV-HCC patients. Kaplan-Meier analysis was used to compare the survival differences between patients with low and high ccf-mtDNA content. In a hospital-based cohort with 141 HBV-HCC patients, there was no statistically significant association between the ccf-mtDNA content and the overall survival of HBV-HCC patients in the univariate analysis, but a borderline significant association was found in the multivariate analyses. In a subcohort of 50 HBV-HCC patients who received TACE and TCM treatment, high ccfDNA content conferred an increased death risk with a hazard ratio of 4.01 (95% confidence interval: 1.25-12.84, p = 0.019) in the multivariate analysis. Kaplan-Meier survival analysis also showed that patients with high ccf-mtDNA content had unfavorable survival (log rank p = 0.097). Our findings suggest that ccf-mtDNA content is a potential non-invasive prognostic biomarker in HCC patients receiving TACE and TCM treatment.

Effect of humic acid on uranium(VI) retention and transport through quartz columns with varying pH and anion type.

Humic acid (HA)1 is ubiquitous in the environment and is an important factor in the migration behavior of U(VI) in the geological medium. The present work investigated the effect of HA on the migration behavior of U(VI) using quartz column experiments at different pH values and in the presence of various anions. The U(VI) adsorption characteristics and speciation were also studied to illuminate further the migration behavior of U(VI). Our results indicated that, at pH 6.0, HA slightly increased the migration velocity of U(VI) during the initial phase and reduced the quantity of eluted U(VI) because of the formation of HA-U(VI). The relative concentration (c/c0) of U(VI)was higher in the HA-U system at pH 8.0 than that at pH 5.0 because of the higher solubility of HA in basic solutions and the difference in charge of HA-U(VI). In the U-HA-anion system at pH 6.0, the breakthrough pore volumes (PVs2) of U(VI) in electrolytes containing Cl- and SO42- anions (PV = 8) are much higher than for solutions containing phosphate (PV = 3), while the HA migration behavior was not significantly affected by the type of anion. Thus, the fast migration of U(VI) under HA and phosphate was attributed to phosphate rather than HA. This result suggests that phosphate should be given more attention in predictions of U(VI) migration, especially in regions with high groundwater phosphate content.