Liu Yuechen, Liu Zhengyu, Hu Yating, Ling Yunyan, Qing Shunjie, Liu Yang, Zhan Yizhi, Shen Zhiyong, Fang Yuan, Deng Haijun
Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China.
Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China.
Nat Commun. 2025 Jul 1;16(1):5906. doi: 10.1038/s41467-025-60958-0.
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.
结直肠癌（CRC）是一个主要的全球健康问题，发病率排名第三，癌症死亡率排名第二。免疫疗法主要对错配修复缺陷型CRC有效，可能受益于饮食干预。本研究调查了咖啡因在CRC中提高程序性死亡-1（PD-1）免疫疗法疗效的潜力，发现咖啡因通过抑制犬尿氨酸途径显著降低CRC中的肿瘤生长、延长生存期并增强CD8 T细胞活性。从机制上讲，咖啡因通过Krüppel样因子4（KLF4）- XII型胶原α1（COL12A1）- 丝裂原活化蛋白激酶（MAPK）- 吲哚胺2,3-双加氧酶1（IDO1）轴降低犬尿氨酸，减轻CD8 T细胞耗竭。将咖啡因与PD-1疗法联合使用可进一步延长生存期，凸显了将营养策略纳入癌症治疗以改善治疗效果和拓宽治疗选择的价值。在此，我们表明咖啡因可通过抑制犬尿氨酸途径增强CRC中的PD-1免疫疗法，提示其作为辅助饮食疗法的潜力。
