KLHL6 tunes T cell fate to boost cancer immunotherapy

A Nature study identifies the E3 ubiquitin ligase KLHL6 as a dual regulator of CD8+ T cell exhaustion and mitochondrial fitness. KLHL6 promotes TOX poly-ubiquitination and degradation, delaying terminal exhaustion, while also restraining excessive mitochondrial fission via the PGAM5–Drp1 axis to maintain T cell metabolism. TCR stimulation downregulates KLHL6, but enforced KLHL6 expression in adoptively transferred T cells enhances anti-tumor and anti-viral responses, highlighting KLHL6 as a clinically actionable target to improve cancer immunotherapy by tuning proteostasis.