Immunotherapy discovery on tumor organoid-on-a-chip platforms that recapitulate the tumor microenvironment.

Cancer immunotherapy has achieved remarkable success over the past decade by modulating patients' own immune systems and unleashing pre-existing immunity. However, only a minority of cancer patients across different cancer types are able to benefit from immunotherapy treatment; moreover, among those small portions of patients with response, intrinsic and acquired resistance remains a persistent challenge. Because the tumor microenvironment (TME) is well recognized to play a critical role in tumor initiation, progression, metastasis, and the suppression of the immune system and responses to immunotherapy, understanding the interactions between the TME and the immune system is a pivotal step in developing novel and efficient cancer immunotherapies. With unique features such as low reagent consumption, dynamic and precise fluid control, versatile structures and function designs, and 3D cell co-culture, microfluidic tumor organoid-on-a-chip platforms that recapitulate key factors of the TME and the immune contexture have emerged as innovative reliable tools to investigate how tumors regulate their TME to counteract antitumor immunity and the mechanism of tumor resistance to immunotherapy. In this comprehensive review, we focus on recent advances in tumor organoid-on-a-chip platforms for studying the interaction between the TME and the immune system. We first review different factors of the TME that recent microfluidic in vitro systems reproduce to generate advanced tools to imitate the crosstalk between the TME and the immune system. Then, we discuss their applications in the assessment of different immunotherapies' efficacy using tumor organoid-on-a-chip platforms. Finally, we present an overview and the outlook of engineered microfluidic platforms in investigating the interactions between cancer and immune systems, and the adoption of patient-on-a-chip models in clinical applications toward personalized immunotherapy.