Long-standing evidence implicates glioma stem cells (GSC) as the major driver for glioma propagation and recurrence. GSCs have a distinctive metabolic landscape characterized by elevated glycolysis. Lactate accumulation resulting from enhanced glycolytic activity can drive lysine lactylation to regulate protein functions, suggesting that elucidating the lactylation landscape in GSCs could provide insights into glioma biology. Herein, we have demonstrated that global lactylation was significantly elevated in GSCs compared with differentiated glioma cells. Polypyrimidine tract–binding protein 1 (PTBP1), a central regulator of RNA processing, was hyperlactylated in GSCs, and SIRT1 induced PTBP1 delactylation. PTBP1-K436 lactylation supported glioma progression and GSC maintenance. Mechanistically, K436 lactylation inhibited PTBP1 proteasomal degradation by attenuating the interaction with TRIM21. Moreover, PTBP1 lactylation enhanced RNA-binding capacity and facilitated PFKFB4 mRNA stabilization, which further increased glycolysis. Together, these findings uncovered a lactylation-mediated mechanism in GSCs driven by metabolic reprogramming that induces aberrant epigenetic modifications to further stimulate glycolysis, resulting in a vicious cycle to exacerbate tumorigenesis. Significance: Glycolysis-induced lactylation enhances the function of PTBP1 to promote glioma stem cell maintenance, indicating that PTBP1 lactylation could be a potential target for the development of innovative glioma therapies.

Significance: The clinical efficacy of immunotherapy in cancer patients is limited. We have developed a zebrafish model that allows us to visualize the metastatic cancer cell-killing effect by tumor-infiltrating lymphocytes and chimeric antigen receptor T cells in vivo at the single-cell level. This in vivo model accurately predicts clinical efficacy of T cell-mediated cancer therapy. Our data provide an in vivo platform for validating antimetastatic effects by human T cell-mediated immunotherapy. Based on our findings, it is highly recommended that anticancer effects of T cells isolated from cancer patients or genetically propagated T cells should be evaluated in this in vivo animal model before clinical application. If so, millions of cancer patients might benefit from our work.

Cis-Diamminedichloroplatinum (II) (DDP)-induced nephrotoxicity (DDPIN) may cause irreversible renal injury associated with high morbidity and mortality. Current standard therapies have not achieved satisfactory clinical outcomes due to unclear molecular and cellular mechanisms. Therefore, exploring potential therapies on DDPIN represents an urgent medical need. Present study characterized the role of lncRNA maternally expressed gene 3 (lnc-MEG3) in the pathogenesis of DDPIN. In both in vitro and in murine models of DDP-induced nephrotoxicity, lnc-MEG3 exacerbated DDPIN by negatively regulating miRNA-126 subsequently causing a decreased AKT/TSC/mTOR-mediated autophagy. By silencing lnc-MEG3 or incorporating miRNA-126 mimetics, the proliferation and migration of DDP-treated cells were restored. In vivo, we identified Paeonol to alleviate DDPIN by the inhibition of lnc-MEG3. Taken together, lnc-MEG3 represents a novel therapeutic target for DDPIN and Paeonol may serve as a promising treatment by inhibiting lnc-MEG3 and its related signaling pathways.

Cell therapy encompasses an expanding spectrum of cell-based regimes for the treatment of human ailments, such as the use of immune cells, in particular T cells, for combating tumors and the modulation of inflammatory immune responses. In this review, we focus on cell therapy in the immuno-oncology space, which is largely driven by interests and demands from the clinics for better solutions to target various hard-to-treat cancers. We discuss recent advances in various types of cell therapies, including T cell receptor-T cells, chimeric antigen receptor (CAR)-T cells, tumor-infiltrating lymphocytes and natural killer cells. Particularly, the present review focuses on the strategies to improve therapeutic responses by either enhancing tumor recognition or the resilience of infused immune cells within tumor microenvironment. Finally, we discuss the potential of other innate or innate-like immune cell types currently being explored as promising CAR-cell alternatives that seek to address the limitations of conventional adoptive cell therapies.

Chimeric antigen receptor (CAR) cell immunotherapies, including CAR-T, CAR-Macrophages, CAR-Natural Killer, CAR-γδ T, etc., have demonstrated significant advancements in the treatment of both hematologic malignancies and solid tumors. Despite the notable successes of traditional CAR cell manufacturing, its application remains constrained by the complicated production process and expensive costs. Consequently, efforts are focused on streamlining CAR cell production to enhance efficacy and accessibility. Among numerous proposed strategies, direct in vivo generation of CAR cells represents the most substantial technical challenge, yet holding great promise for achieving clinical efficacy. Herein, we outlined the current state-of-the-art in vivo CAR therapy, including CAR technology development, transfection vectors, and influence factors of construction of CAR in vivo. We also reviewed the types and characteristics of different delivery systems and summarized the advantages of in vivo CAR cell therapy, such as rapid preparation and cost-effectiveness. Finally, we discussed the limitations, including technical issues, challenges in target and signal design, and cell-related constraints. Meanwhile, strategies have correspondingly been proposed to advance the development of CAR cell therapy, in order to open the new horizons on cancer treatment.

Nonalcoholic steatohepatitis (NASH) is a chronic, inflammatory form of nonalcoholic fatty liver disease (NAFLD) that frequently progresses to cirrhosis and hepatocellular carcinoma (HCC). However, the role of various immune cells in switching from NAFLD to NASH remains elusive. Here, we took an unbiased single-cell assay for transposase accessible chromatin sequencing (scATAC-seq) approach to investigate the cellular composition, gene expression profiling, and causative roles of immune cells in NASH development. T helper 17 (T _H 17) cells were identified as the most abundant subpopulation of immune cells in mouse livers with NASH. Further analysis of scATAC-seq data and single-cell RNA sequencing (scRNA-seq) data from the GEO database showed that human immunodeficiency virus type I enhancer binding protein 1 (HIVEP1) is a critical transcription factor (TF) regulating T _H 17 cell differentiation and cytokine production. Specific knockout of Hivep1 in IL-17A ⁺ and CD4 ⁺ T cells in mice showed impairment of T _H 17 cell differentiation and alleviation of NASH development. Mechanistically, HIVEP1 transcriptionally regulated ornithine decarboxylase 1 (ODC1), the rate-limiting enzyme of polyamine metabolism, to modulate T _H 17 cell differentiation and cytokine production. Consequently, pharmacological inhibition of ODC1 decreased cytokine production, alleviated inflammation, and prevented the NAFLD-to-NASH transition. Together, our findings elucidate the role of polyamine metabolism in T _H 17 cell–mediated NASH development and identify potential therapeutic targets for the effective treatment of NASH.