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

Introduction

Colorectal cancer (CRC) ranks as the third most common cancer worldwide and is the second leading cause of cancer-related deaths^1,2. Although immunotherapy represents a significant breakthrough in cancer treatment, its benefits are not yet universal among CRC patients. At present, only CRC patients with mismatch repair deficiency or high microsatellite instability (MSI-H) benefit from immune checkpoint inhibitors^3,4. Importantly, only 15% of CRC cases are MSI-H, and this percentage decreases to 4 ~ 5% in advanced stages⁵. Therefore, it is crucial to expand the scope of CRC immunotherapy to benefit a broader patient population or combine other treatments to boost immunotherapy.

Tumor development and progression are strongly influenced by dietary habits. Dietary interventions can aid tumor treatment by limiting tumor nutrition, boosting drug efficacy, and enhancing the immune microenvironment^{6, 7–8}. Research indicates that diets rich in serine and glycine may accelerate colorectal cancer progression through the induction of KRAS and TP53 mutations⁹. Diets high in methionine may foster colorectal cancer growth by activating the immune microenvironment via m⁶A methylation in tumor cells¹⁰. Diets containing mannose can impede colorectal cancer metastasis by inhibiting fructose metabolism¹¹. Thus, dietary interventions are vital in managing colorectal cancer and could potentially enhance the effectiveness of immunotherapy. The role of dietary components in influencing immunotherapy for colorectal cancer remains to be further investigated.

Coffee is a staple beverage worldwide. Numerous studies suggest that coffee may help prevent colorectal cancer, offering potential health benefits^{12, 13–14}. Although a cup of coffee contains hundreds of compounds, the levels of which can vary due to different production and preparation processes, caffeine is the primary component across various coffee types. Caffeine, a purine alkaloid, has been reported to inhibit intestinal inflammation and regulate the gut microbiome, potentially lowering the risk of colorectal cancer^15,16. Additionally, caffeine inhibits the adenosine A2A receptor, reducing adenosine’s immunosuppressive effects and enhancing macrophages’ phagocytic and antitumor activities¹⁷. Research combining caffeine with anti-PD-1 therapy in melanoma has shown that this treatment can effectively inhibit melanoma growth and significantly increase CD4⁺ and CD8⁺ T lymphocyte infiltration¹⁸. However, what effect caffeine has on colorectal cancer and the specific mechanism remains unknown.