The failure of T cells to eradicate tumour cells in the tumour microenvironment is mainly due to the dysfunction of T cells. Senescent T cells, with defects in proliferation and effector functions, accumulate in ageing, chronic viral infections, and autoimmune disorders where antigen stimulation persists. Increasing evidence suggests that inducing T cell senescence is a key strategy used by malignant tumours to evade immune surveillance. In this review, we summarize the general features, functional regulation, and signalling network of senescent T cells in tumour development and highlight their potential as prognostic biomarkers in multiple cancer treatments, including chemotherapy, radiotherapy, and immunotherapy. Moreover, we discuss possible therapeutic strategies for preventing or rejuvenating senescence in tumour-specific T cells. Understanding these critical issues may provide novel strategies to enhance cancer immunotherapy.

Pembrolizumab, an anti‐programmed cell death protein 1 (PD‐1) antibody, has been shown to improve survival in patients with non‐small cell lung cancer (NSCLC) with high expression of programmed death‐ligand 1 (PD‐L1). Corticosteroids are the mainstay for most high‐grade immune‐related adverse events (irAEs) such as pembrolizumab‐induced hepatitis. However, the dose and duration of corticosteroid therapy are not well defined. The objective of this case report was to describe a new treatment pattern for severe immune checkpoint inhibitor‐associated hepatitis. Here, we report the case of a patient with metastatic lung adenocarcinoma who developed grade 3 immunotherapy‐induced hepatitis after the first cycle of pembrolizumab. Alanine aminotransferase (ALT) levels peaked at 233 U/L. Hepatitis was alleviated after the administration of methylprednisolone. Therefore, we retreated the patient with pembrolizumab. However, aminotransferase levels increased again after the initiation of low‐dose methylprednisolone or the reuse of pembrolizumab. Finally, hepatitis was controlled with low‐dose methylprednisolone plus bicyclol, a Chinese hepatoprotective agent. Although the patient had been on low‐dose methylprednisolone therapy for about six months, he showed a prompt response. During this period, we also found a dramatic decrease in the neutrophil‐lymphocyte ratio (NLR), senescent T cells (CD8⁺CD28⁻CD57⁺), and myeloid‐derived suppressor cells (MDSCs) in the peripheral blood of the patient. To our knowledge, this is the first case report of successful management of grade 3 pembrolizumab‐induced hepatitis with a combination of low‐dose corticosteroids and bicyclol. The durable clinical response and changes in blood biomarkers indicate that low doses of corticosteroids do not compromise the efficacy of immune checkpoint inhibitors (ICIs). Therefore, this case may provide a new treatment pattern for severe immunotherapy‐induced hepatitis.

Background/Objectives: Lipid metabolism plays a crucial role in uterine corpus endometrial carcinoma (UCEC); however, its specific mechanisms remain to be fully elucidated. This study aimed to construct a lipid-metabolism-related prognostic model and explore its association with the tumor immune microenvironment. Methods: A total of 552 UCEC and 35 normal tissue samples from The Cancer Genome Atlas (TCGA) database were analyzed to identify differentially expressed lipid-metabolism-related genes (DE-LMRGs). A prognostic risk model was established using univariate Cox analysis, least absolute shrinkage and selection operator (LASSO) regression, and multivariate Cox regression, and its clinical utility was assessed through nomogram construction. Functional enrichment analysis was performed to explore the biological pathways involved. Tumor immune infiltration patterns were evaluated using single-sample Gene Set Enrichment Analysis (ssGSEA), Estimation of Stromal and Immune Cells in Malignant Tumors using Expression Data (ESTIMATE), and Tumor Immune Dysfunction and Exclusion (TIDE) algorithms. Results: Multivariate analysis indicated that the prognostic model had robust predictive value, with AUCs of 0.701, 0.746, and 0.790 for 1-, 3-, and 5-year overall survival predictions. High-risk patients exhibited a suppressed immune microenvironment characterized by reduced immune cell infiltration, lower tumor mutation burden (TMB), and elevated TIDE scores, suggesting potential resistance to immunotherapy. Furthermore, LIPG was identified as a key hub gene through the intersection of nine machine learning algorithms, demonstrating strong associations with both cancer progression and immune infiltration. Functional validation using Cell Counting Kit-8 (CCK-8), wound healing, and transwell migration assays following small interfering RNA (siRNA) transfection demonstrated that LIPG promotes UCEC cell proliferation and migration in vitro. Conclusions: These findings highlight the critical role of lipid metabolism in UCEC progression and immune modulation, with LIPG emerging as a potential prognostic biomarker. The identified lipid-metabolism-related gene signature may provide new insights into tumor microenvironment interactions.

In late 2022, Beijing, China saw a large-scale BF.7 Omicron variant breakthrough infection. However, the impact of COVID-19 vaccines on elderly breakthrough-infected patients’ antibodies and immune cells response was unclear. We recruited 329 inpatients over 65 with BF.7 breakthrough infections. We analyzed the link between vaccination and survival in 67 sampled patients, investigating changes in antibody levels, cytokine profiles, as well as immune phenotypes. Experiments revealed that while vaccination could raise antibody levels in the elderly, it showed no significant neutralizing activity against the emerging COVID-19 variant XBB. Flow cytometry showed vaccination increased the proportion of CD4+ senescent T cells. Moreover, we found that elevated frequencies of CD4+ Tsens cells were associated with reduced antigen-specific CD4+ T cell activation, diminished IL-2 production, and lower proportions of Tfh cells, which ultimately leading to impaired neutralizing antibody production, particularly against new emerging variants. We found the immunological efficacy of inactivated vaccines in elderly patients is influenced by the proportion of CD4+ senescent T cells. Future elderly vaccination strategies need optimization in dose number and timing, and future vaccine design should aim to minimize the generation of CD4+ senescent T cells.

Single-cell metabolic characteristics are powerful indicators of cellular physiological and pathological states. Flow cytometry enables high-throughput single-cell metabolic profiling and immunophenotyping; however, spectral overlap impedes simultaneous detection of multi-parametric features. This limitation imposes larger sample requirements and increased variabilities due to metabolic dynamics-constraints acutely magnified in studies utilizing clinical microsamples. To overcome these shortcomings, we developed a spectral flow cytometry platform for immunometabolic features, using 13 dual-probe combinations and 11 fluorophore probes. Requiring only 100 μL of whole blood per assay, this platform enables concurrent detection of 4 metabolic biomarkers and 16 immune markers. Application to patients with heart failure revealed heterogeneous metabolic landscapes across 20 immune subpopulations, showing reduced frequencies of naive T cells and NK-like T cells, with a metabolic shift from fatty acid dependence to glucose avidity. Our framework captures metabolic interactions previously inaccessible by sequential detection and will help to enable precision immunometabolism research.

The newly generated CD4 single-positive (SP) T lymphocytes are featured by enhanced IL-4 but repressed IFN-γ production. The mechanisms underlying this functional bias remain elusive. Previous studies have reported that CD4⁺ T cells from mice harboring dendritic cell (DC)-specific deletion of IL-27p28 display an increased capacity of IFN-γ production upon TCR stimulation. Here, we demonstrated that similarly altered functionality occurred in CD4SP thymocytes, recent thymic emigrants (RTEs), as well as naive T cells from either Cd11c-p28^f/f mice or mice deficient in the α subunit of IL-27 receptor. Therefore, DC-derived IL-27p28-triggered, IL-27Rα-mediated signal is critically involved in the establishment of functional bias against IFN-γ production during their development in the thymus. Epigenetic analyses indicated reduced DNA methylation of the Ifng locus and increased trimethylation of H3K4 at both Ifng and Tbx21 loci in CD4SP thymocytes from Cd11c-p28^f/f mice. Transcriptome profiling demonstrated that Il27p28 ablation resulted in the coordinated up-regulation of STAT1-activated genes. Concurrently, STAT1 was found to be constitutively activated. Moreover, we observed increased accumulation of STAT1 at the Ifng and Tbx21 loci and a strong correlation between STAT1 binding and H3K4me3 modification of these loci. Of note, Il27p28 deficiency exacerbated the autoimmune phenotype of Aire^-/- mice. Collectively, this study reveals a novel mechanism underlying the functional bias of newly generated CD4⁺ T cells and the potential relevance of such a bias in autoimmunity.