As one of the diseases associated with aging, cancer has received much attention. Since its discovery, interleukin-27 (IL-27), a unique cytokine, has garnered increasing attention due to its immune-regulatory functions. Initially studied primarily for its role in immune responses, the involvement of IL-27 in cancer development and progression remains underexplored. This study investigates the evolving understanding of IL-27 and its connection to various cancers. Our findings reveal a growing body of research on IL-27’s role in cancer from 2002 to 2023, with a notable increase in focus on its immune-modulatory properties after 2007. We identified key research contributors and collaborations worldwide that have driven progress in this field. Notably, the shift in research emphasis from basic immune regulation to the tumor immune microenvironment has highlighted IL-27’s potential significance in cancer biology. Our analysis shows a strong correlation between IL-27 expression levels and the prognosis of several cancers, including lung and breast cancers, suggesting its pivotal role in modulating immune responses within the tumor microenvironment. Furthermore, IL-27 has emerged as a promising biomarker for cancer prognosis and a potential target for immunotherapy. These findings underscore IL-27’s critical involvement in cancer biology and position it as a key molecule in future therapeutic strategies.