Nature：李贵登团队发现癌症免疫治疗新靶点——KLHL6，有望增强T细胞疗法抗癌效果

Core Viewpoint - The study highlights the role of the E3 ubiquitin ligase KLHL6 as a dual negative regulator of T cell exhaustion and mitochondrial dysfunction during chronic antigen stimulation, suggesting its potential as a clinical target to enhance cancer immunotherapy effectiveness [5][7][9]. Group 1: T Cell Dysfunction and Mechanisms - T cell dysfunction, including exhaustion and mitochondrial impairment, is a major barrier in cancer immunotherapy [7]. - The research combines computational analysis with in vivo CRISPR screening to identify KLHL6 as a key factor in regulating T cell exhaustion and mitochondrial health [5][7]. - KLHL6 expression promotes the polyubiquitination and subsequent proteasomal degradation of the exhaustion core regulator TOX, inhibiting the transition from precursor exhausted T cells (Tpex) to terminal exhausted T cells (Tex-term) [7][9]. Group 2: Therapeutic Implications - Enhancing KLHL6 expression in T cells significantly improves anti-tumor and anti-viral efficacy, indicating its critical role in T cell fate and function [5][8]. - The study suggests a new therapeutic approach to restore or enhance KLHL6 expression to reverse T cell exhaustion during chronic TCR stimulation [8][9]. - The findings underscore the potential of targeting protein homeostasis and ubiquitination modifications to improve immunotherapy outcomes [9][10].