REVIEW article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
This article is part of the Research TopicAdvancing Next-Generation Immunotherapy and Biomarker Discovery: Pioneering the Future of Treatment Strategies in Solid TumorsView all 6 articles
Terminally exhausted CD8+ T cells in solid tumors: Biology, biomarker potential and translational tools for precision oncology
Provisionally accepted
- 1Puyang Oilfield General Hospital, Puyang, China
- 2China Medical University - The Queen's University of Belfast Joint College, Shenyang, China
- 3University of California, San Diego, La Jolla, United States
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Terminally exhausted CD8⁺ T cells (Ttex) are emerging as clinically relevant immune subsets across solid tumors, marked by sustained inhibitory receptor expression, loss of TCF1, and limited proliferative capacity. Once considered functionally inert, Ttex are now recognized for their residual cytotoxic potential and strong associations with tumor immunogenicity, including microsatellite instability (MSI), high tumor mutational burden (TMB), and neoantigen load. Importantly, the prognostic significance of Ttex is highly tumor-context-dependent, shaped by stromal architecture, mutational burden, and progenitor Tpex availability. This review examines the biology, spatial localization, and prognostic value of Ttex, highlighting the Ttex/CD8⁺ ratio as a promising biomarker in cancers such as colorectal, lung, and esophageal carcinoma. We summarize recent advances in multiplex imaging, digital pathology, and AI-driven quantification that support the clinical integration of Ttex assessment. In addition, we discuss emerging therapeutic strategies targeting Ttex through immune checkpoint combinations, thymocyte selection-associated high mobility group box protein (TOX) and circRNA-mediated reprogramming, and exhaustion-resistant T cell engineering. Finally, we outline translational priorities including assay harmonization, functional validation, and longitudinal profiling to advance Ttex-based precision oncology.
Keywords: digital pathology, immunotherapy biomarkers, precision oncology, t cell exhaustion, Terminally exhausted CD8⁺ T cells, Tumor Microenvironment
Received: 21 Sep 2025; Accepted: 12 Dec 2025.
Copyright: © 2025 Guo, Ma, Wang, Fu and Ma. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Wenxue Ma
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