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A steady dysfunctional state caused by chronic antigen stimulation in the tumor microenvironment (TME) is known as CD8 T cell exhaustion. Exhausted-like CD8 T cells (CD8 Tex) displayed decreased effector and proliferative capabilities, elevated co-inhibitory receptor generation, decreased cytotoxicity, and changes in metabolism and transcription. TME induces T cell exhaustion through long-term antigen stimulation, upregulation of immune checkpoints, recruitment of immunosuppressive cells, and secretion of immunosuppressive cytokines. CD8 Tex may be both the reflection of cancer progression and the reason for poor cancer control. The successful outcome of the current cancer immunotherapies, which include immune checkpoint blockade and adoptive cell treatment, depends on CD8 Tex. In this review, we are interested in the intercellular signaling network of immune cells interacting with CD8 Tex. These findings provide a unique and detailed perspective, which is helpful in changing this completely unpopular state of hypofunction and intensifying the effect of immunotherapy.
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http://dx.doi.org/10.3389/fimmu.2024.1476904 | DOI Listing |
Mol Ther
September 2025
Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China; Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China. Electronic address:
The reduction of TCF-1 during CD8 T cell exhaustion leads to attenuated antitumor activity and diminished responsiveness to immune checkpoint inhibitors. However, how TCF-1 is downregulated remains unclear. Here, we showed that during CD8 T cell exhaustion, lnc-SUMF2-8, induced by transcription factor TOX, can bind to cytosolic TCF-1, and direct it to the lysosome for degradation.
View Article and Find Full Text PDFCancer Cell
July 2025
Department of Lymphoma and Myeloma, University of Texas (UT) MD Anderson Cancer Center, Houston, TX, USA; Lymphoid Malignancies Program, UT MD Anderson Cancer Center, Houston, TX, USA; Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX, USA. Electronic address: mgreen5@mdander
Large B cell lymphomas (LBCL) are clinically and biologically heterogeneous lymphoid malignancies with complex microenvironments that are central to disease etiology. Here, we have employed single-nucleus multiome profiling of 232 tumor and control biopsies to characterize diverse cell types and subsets that are present in LBCL tumors, effectively capturing the lymphoid, myeloid, and non-hematopoietic cell compartments. Cell subsets co-occurred in stereotypical lymphoma microenvironment archetype profiles (LymphoMAPs) defined by; (1) a sparsity of T cells and high frequencies of cancer-associated fibroblasts and tumor-associated macrophages (FMAC); (2) lymph node architectural cell types with naive and memory T cells (LN); or (3) activated macrophages and exhausted CD8 T cells (TEX).
View Article and Find Full Text PDFOncol Rep
November 2025
Department of Oncology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China.
Lung adenocarcinoma (LUAD) is one of the most common malignancies in the lung. T cell exhaustion (TEX) is an important immune escape mechanism that may be targeted to improve tumor immunotherapy. The present study investigated TEX‑related genes in the tumor microenvironment to predict the prognosis of patients with LUAD.
View Article and Find Full Text PDFbioRxiv
August 2025
Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania; Philadelphia, PA, USA.
Persistent antigen stimulation promotes differentiation of exhausted CD8 T (T) cells. T cells are distinct from circulating memory T (T) cells but share many features with tissue-resident memory (T) cells established following infection resolution. CD8 T cells co-expressing residency- and exhaustion-associated molecules in chronic diseases often correlate with clinical outcomes.
View Article and Find Full Text PDFNat Commun
August 2025
Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
T-cell exhaustion contributes to immunotherapy failure in chronic lymphocytic leukemia (CLL). Here, we analyze T cells from CLL patients' blood, bone marrow, and lymph nodes, as well as from a CLL mouse model, using single-cell RNA sequencing, mass cytometry, and tissue imaging. T cells in CLL lymph nodes show the most distinct profiles, with accumulation of regulatory T cells and CD8 T cells in various exhaustion states, including precursor (T) and terminally exhausted (T) cells.
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