Yue Zheng

Metformin is a well-known anti-diabetic drug that has been repurposed for several emerging applications, including as an anti-cancer agent. It boasts the distinct advantages of an excellent safety and tolerability profile and high cost-effectiveness at less than one US dollar per daily dose. Epidemiological evidence reveals that metformin reduces the risk of cancer and decreases cancer-related mortality in patients with diabetes; however, the exact mechanisms are not well understood. Energy metabolism may be central to the mechanism of action. Based on altering whole-body energy metabolism or cellular state, metformin's modes of action can be divided into two broad, non-mutually exclusive categories: "direct effects", which induce a direct effect on cancer cells, independent of blood glucose and insulin levels, and "indirect effects" that arise from systemic metabolic changes depending on blood glucose and insulin levels. In this review, we summarize an updated account of the current knowledge on metformin antitumor action, elaborate on the underlying mechanisms in terms of the hallmarks of cancer, and propose potential applications for repurposing metformin for cancer therapeutics.

Metabolic reprogramming of amino acids has been increasingly recognized to initiate and fuel tumorigenesis and survival. Therefore, there is emerging interest in the application of amino acid metabolic strategies in antitumor therapy. Tremendous efforts have been made to develop amino acid metabolic node interventions such as amino acid antagonists and targeting amino acid transporters, key enzymes of amino acid metabolism, and common downstream pathways of amino acid metabolism. In addition to playing an essential role in sustaining tumor growth, new technologies and studies has revealed amino acid metabolic reprograming to have wide implications in the regulation of antitumor immune responses. Specifically, extensive crosstalk between amino acid metabolism and T cell immunity has been reported. Tumor cells can inhibit T cell immunity by depleting amino acids in the microenvironment through nutrient competition, and toxic metabolites of amino acids can also inhibit T cell function. In addition, amino acids can interfere with T cells by regulating glucose and lipid metabolism. This crucial crosstalk inspires the exploitation of novel strategies of immunotherapy enhancement and combination, owing to the unprecedented benefits of immunotherapy and the limited population it can benefit. Herein, we review recent findings related to the crosstalk between amino acid metabolism and T cell immunity. We also describe possible approaches to intervene in amino acid metabolic pathways by targeting various signaling nodes. Novel efforts to combine with and unleash potential immunotherapy are also discussed. Hopefully, some strategies that take the lead in the pipeline may soon be used for the common good.

Objective To explore the impact of sports on aggression in children and adolescents and analyze whether different conditions in the intervention, such as type of sports, or intervention duration, have different influences on the effect of interventions. Method The study protocol was registered in PROSPERO (CRD42022361024). We performed a systematic search of Pubmed, Web of Science, Cochrane library, Embase and Scopus databases from database inception to 12 October 2022 for all studies written in English. Studies were included if they met the following PICO criteria. All analyses were carried out using the Review Manager 5.3 Software. We summarized aggression, hostility and anger scores using SMDs. Summary estimates with 95% confidence intervals were pooled using DerSimonian-Laird random effects model or fixed effects model according to between-study heterogeneity. Results A total of 15 studies were deemed eligible for inclusion in this review. The overall mean effect size indicated that sport interventions was associated with lower aggression (SMD = −0.37, 95% CI [−0.69 to −0.06], P = 0.020; I 2 = 88%). Subgroup analyses showed that non-contact sports were associated with lower aggression (SMD = −0.65, 95% CI [−1.17 to −0.13], P = 0.020; I 2 = 92%) but high-contact sports were not (SMD = −0.15, 95% CI [−0.55 to 0.25], P = 0.470; I 2 = 79%). In addition, when intervention duration <6 months, sport interventions was associated with lower aggression (SMD = −0.99, 95% CI [−1.73 to −0.26], P = 0.008; I 2 = 90%) and when intervention duration ≥ 6 months, sport interventions was not associated with lower aggression (SMD = −0.08, 95% CI [−0.44 to −0.28], P = 0.660; I 2 = 87%). Conclusion This review confirmed that sports intervention can reduce the aggression of children and adolescents. We suggested that schools can organize young people to participate in low-level, non-contact sports to reduce the occurrence of bullying, violence and other aggression-related adverse events. Additional studies are needed to determine which other variables are associated with aggression in children and adolescents, in order to develop a more detailed and comprehensive intervention programme to reduce their aggression.

Adoptive immunotherapy in the T cell landscape exhibits efficacy in cancer treatment. Over the past few decades, genetically modified T cells, particularly chimeric antigen receptor T cells, have enabled remarkable strides in the treatment of hematological malignancies. Besides, extensive exploration of multiple antigens for the treatment of solid tumors has led to clinical interest in the potential of T cells expressing the engineered T cell receptor (TCR). TCR-T cells possess the capacity to recognize intracellular antigen families and maintain the intrinsic properties of TCRs in terms of affinity to target epitopes and signal transduction. Recent research has provided critical insight into their capability and therapeutic targets for multiple refractory solid tumors, but also exposes some challenges for durable efficacy. In this review, we describe the screening and identification of available tumor antigens, and the acquisition and optimization of TCRs for TCR-T cell therapy. Furthermore, we summarize the complete flow from laboratory to clinical applications of TCR-T cells. Last, we emerge future prospects for improving therapeutic efficacy in cancer world with combination therapies or TCR-T derived products. In conclusion, this review depicts our current understanding of TCR-T cell therapy in solid neoplasms, and provides new perspectives for expanding its clinical applications and improving therapeutic efficacy.

BACKGROUND: Neoadjuvant immunotherapy is under intensive investigation for esophageal squamous cell carcinoma (ESCC). This study assesses the efficacy and immune response of neoadjuvant immunochemotherapy (nICT) in ESCC. METHODS: In this phase II trial (ChiCTR2100045722), locally advanced ESCC patients receiving nICT were enrolled. The primary endpoint was the pathological complete response (pCR) rate. Multiplexed immunofluorescence, RNA-seq and TCR-seq were conducted to explore the immune response underlying nICT. RESULTS: Totally 42 patients were enrolled, achieving a 27.0% pCR rate. The 1-year, 2-year DFS and OS rates were 89.2%, 64.4% and 97.3%, 89.2%, respectively. RNA-seq analysis highlighted T-cell activation as the most significantly enriched pathway. The tumour immune microenvironment (TIME) was characterised by high CD4, CD8, Foxp3, and PD-L1 levels, associating with better pathological regression (TRS0/1). TIME was categorised into immune-infiltrating, immune-tolerant, and immune-desert types. Notably, the immune-infiltrating type and tertiary lymphoid structures correlated with improved outcomes. In the context of nICT, TIM-3 negatively influenced treatment efficacy, while elevated TIGIT/PD-1 expression post-nICT correlated positively with CD8+ T cell levels. TCR-seq identified three TCR rearrangements, underscoring the specificity of T-cell responses. CONCLUSIONS: Neoadjuvant camrelizumab plus chemotherapy is effective for locally advanced, resectable ESCC, eliciting profound immune response that closely associated with clinical outcomes.