Deoxycholic acid impairs mitochondrial fitness and suppresses mitophagy through Parkin ubiquitination driving CD8+ T cell Exhaustion in Colorectal Cancer.

Colorectal cancer (CRC) exhibits significant heterogeneity in response to immunotherapy that cannot be fully explained by microsatellite status alone. Although elevated bile acid levels are recognized as an important risk factor for CRC, their impact on immunotherapy responsiveness remains poorly understood. Here, we demonstrate that high bile acid levels profoundly impair anti-PD-1 efficacy in both CRC patient cohort and mouse models, accompanied by reduced infiltration and functional impairment of tumor-infiltrating CD8+ T cells. Bile acid profiling identified deoxycholic acid (DCA) as the key bile acid species mediating this immunosuppressive effect. In vitro and in vivo studies have shown that DCA not only suppressed CD8+ T cell effector function but also drove them toward terminal exhaustion, thereby limiting responsiveness to anti-PD-1. Mechanistically, DCA disrupted mitochondrial fitness in CD8+ T cells by suppressing oxidative phosphorylation and inducing excessive mitochondrial reactive oxygen species (mtROS) production. In parallel, DCA enhanced ubiquitination-dependent degradation of Parkin, thereby inhibiting mitophagy and causing the accumulation of damaged mitochondria. These convergent defects in mitochondrial homeostasis ultimately promoted CD8+ T cell dysfunction and terminal exhaustion. Notably, pharmacological reactivation of mitophagy via Urolithin A reversed these defects and restored the antitumor efficacy of anti-PD-1 in vivo. Collectively, our findings identified a DCA-Parkin-mitophagy axis that drives CD8+ T cell terminal exhaustion and compromises immunotherapy efficacy, providing a potential metabolic intervention strategy to improve immunotherapy responses in CRC patients with elevated bile acid levels.