Caffeine enhances antitumor T-cell activity by suppressing kynurenine pathway in colorectal cancer

作者：Y. Liu, Zhengyu Liu, Yating Hu, Yunyan Ling, Shunjie Qing, Yang Liu, Yizhi Zhan, Zhiyong Shen, Yuan Fang, Haijun Deng · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-60958-0 · 被引用次数：13 · 研究领域：Epigenetics and DNA Methylation、Adenosine and Purinergic Signaling、Cannabis and Cannabinoid Research

Colorectal cancer (CRC) is a leading global health issue, ranking third in incidence and second in cancer mortality. Immunotherapy, effective mainly in mismatch repair-deficient CRC, may benefit from dietary interventions. This study investigates caffeine’s potential to boost programmed death-1 (PD-1) immunotherapy efficacy in CRC, revealing that caffeine significantly reduces tumor growth, extends survival, and enhances CD8+ T cell activity in CRC by suppressing kynurenine pathway. Mechanistically, caffeine decreases kynurenine via the Krüppel-like factor 4 (KLF4)- Collagen type XII alpha 1 (COL12A1)- Mitogen-Activated Protein Kinase (MAPK)-Indoleamine 2,3-dioxygenase 1 (IDO1) axis, mitigating CD8+ T cell exhaustion. Combining caffeine with PD-1 therapy further prolongs survival, highlighting the value of integrating nutritional strategies into cancer treatment to improve outcomes and broaden therapeutic options. Here, we show caffeine can enhance PD-1 immunotherapy in CRC by suppressing kynurenine pathway, suggesting its potential as an adjunctive dietary therapy. Coffee has been associated with reduced colorectal cancer incidence. Here, the authors show that caffeine inhibits the kynurenine pathway, boosting CD8+ T-cell immunogenic activity, which impairs colorectal cancer progression and enhances immunotherapy response.