From guardians to traitors: molecular mechanisms of tumor-induced T cell betrayal
Year: 2026
Type: article
Abstract: As the core effector cells of the adaptive immune system, T cells play a crucial role in the body's anti-tumor immune responses. However, various toxic factors widely present in the tumor microenvironment (TME), including metabolic abnormalities, mitochondrial transfer phenomena, and diverse toxic mediators, can exert "poisoning" effects on T cells through complex and diverse mechanisms, consequently leading to T cell intoxication. In this state, their roles within the TME undergo profound transformation, with exhaustion being the most typical manifestation. This exhaustion is characterized by loss of anti-tumor function, metabolic dysfunction, and high expression of inhibitory receptors, thereby exacerbating tumor progression. However, studies have revealed that as tumor poisoning intensifies, certain specialized T cell subsets not only exhibit functional impairment but can also actively promote tumor progression through mechanisms such as cytokine secretion and recruitment of tumor-associated cells-a phenomenon defined as T cell betrayal. This review comprehensively and systematically summarizes the patterns of T cell fate transformation during tumor development and provides an in-depth analysis of the essential characteristics of T cell intoxication and betrayal, including their phenotypic features, functional alterations, and their impact on the tumor microenvironment and immunotherapy. Particular emphasis is placed on analyzing the molecular integrative mechanisms by which tumor cells and other cells in the microenvironment poison T cells and induce their intoxication or betrayal through multiple pathways. Furthermore, this review systematically examines therapeutic strategies for reversing T cell betrayal phenomena, including metabolic intervention and microenvironmental modulation, as well as optimization strategies for conventional immunotherapies. This review further explores future directions for achieving a systematic and holistic understanding of the T cell "intoxication-betrayal" framework and examines the potential application value of cutting-edge technologies in this field, aiming to provide novel insights for tumor immunotherapy.
Source: Molecular Cancer
Authors: Pengxi Ye, Hongyu Kuang, Anqi Lin, Bufu Tang, Qi Wang, Hao Zhang, Hank Z. H. Wong, Jian Zhang, Quan Cheng, Antonino Glaviano, Tian Yang, Huaan Du, Peng Luo
Institutions: Zhujiang Hospital, Kangda College of Nanjing Medical University, Southern Medical University, Chongqing Medical University, Fudan University, Zhongshan Hospital, Shanghai Jiao Tong University, Ruijin Hospital, Second Affiliated Hospital of Chongqing Medical University, University of Hong Kong, Central South University, Xiangya Hospital Central South University, University of Palermo, Second Military Medical University, Eastern Hepatobiliary Surgery Hospital
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,090
OpenAlex ID: W7160775449