From guardians to traitors: molecular mechanisms of tumor-induced T cell betrayal

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.