The design and application of microfluidic immune system-on-a-chip (ISOC) technology have played a critical role in cancer immunology and drug discovery over the past decades. The system provides a highly controlled and physiologically relevant platform for studying immune responses and therapeutic interventions. Emerging trends in 3D bioprinting, organoid fusion, and multi-organ systems-on-a-chip further expand the capabilities of ISOC by enabling systemic immune interactions and modeling of the tumor microenvironment. Despite these advances, scalability, standardization, and long-term immune cell viability remain significant challenges that must be addressed to fully harness the potential of ISOC in clinical applications. Overall, ISOC represents a transformative tool in cancer research, offering innovative solutions for immunotherapy trials, biomarker discovery, and precision medicine. Therefore, in this study, the role of ISOC in cancer immunotherapy was investigated, focusing on its ability to recapitulate primary and secondary immune functions, model immune-tumor interactions, and enhance screening and optimization of immune-based therapies. Device design and modeling strategies were also discussed, demonstrating how ISOC platforms simulate dynamic immune cell activity, cytokine signaling, and antigen presentation to improve drug efficacy assessments. The application of ISOC technology in drug discovery and its potential to accelerate clinical trials and develop personalized immunotherapy were further explored.