Organoid and organ-on-a-chip models for the tumor immune microenvironment: A call to incorporate immunosenescence

Abstract

The tumor immune microenvironment (TIME) is a central determinant of cancer progression and therapeutic response. Although organoid and organ-on-a-chip technologies have substantially advanced the modeling of tumor-immune interactions, most current platforms overlook a critical dimension of clinical reality: immunosenescence. This process profoundly reshapes immune cell composition, functional capacity, and tumor-immune crosstalk, yet it remains largely absent from existing in vitro systems. In this review, we provide a conceptual and methodological overview of organoid- and microfluidic-based models for reconstructing the TIME. We highlight their respective strengths in capturing tumor heterogeneity and dynamic immune processes, while critically evaluating their limitations in modeling long-term immune evolution and age-associated dysfunction. Importantly, we propose immunosenescence as a missing but essential modeling axis and argue that it should be treated as a controllable experimental variable rather than a background condition. By integrating aging-associated immune features into advanced 3D and microfluidic platforms, next-generation models are poised to better recapitulate patient heterogeneity and improve the prediction of immunotherapy outcomes. This perspective underscores a shift toward age-aware, physiologically relevant tumor models and provides a framework for advancing precision immuno-oncology in an aging population.