Leveraging Microphysiological Systems to Facilitate Neutrophil-Based Cancer Immunotherapy

Neutrophils are the most abundant immune cells in human blood and serve as the first line of defense against infection. However, the role of neutrophils in cancer progression is complex and context-dependent, and they are underexplored as therapeutic targets for cancer compared with other immune cell types. Microphysiological systems, also known as complex in vitro models, have emerged as powerful tools for deciphering immune cell-cancer interactions and preclinical drug testing due to the advantages of real-time visualization of cell behaviors, precise control of microenvironments, and incorporation of human cells over in vivo animal models. This review first summarizes the multifaceted roles of neutrophils in cancer as defined by in vivo animal models and highlights recently developed strategies to mobilize neutrophils for cancer treatment. Next, current applications of different types of microphysiological systems, including 3D spheroids, organoids, and microfluidic organ-on-a-chip platforms, for investigating the role of human neutrophils in cancer and evaluating neutrophil-based cancer immunotherapies are surveyed. Lastly, future opportunities for microphysiological systems to address key challenges in the clinical translation of neutrophil-based cancer immunotherapy are discussed.