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

Yuechen Liu, Zhengyu Liu, Yating Hu, Yunyan Ling, Shunjie Qing, Yang Liu, Yizhi Zhan, Zhiyong Shen (), Yuan Fang () and Haijun Deng ()
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Yuechen Liu: Southern Medical University
Zhengyu Liu: Southern Medical University
Yating Hu: Southern Medical University
Yunyan Ling: Southern Medical University
Shunjie Qing: Southern Medical University
Yang Liu: Southern Medical University
Yizhi Zhan: Southern Medical University
Zhiyong Shen: Southern Medical University
Yuan Fang: Southern Medical University
Haijun Deng: Southern Medical University

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-60958-0

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