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Preclinical models capable of probing patient-specific tumor-immune interactions are particularly attractive candidates for interrogating mechanisms of resistance, developing predictors of response as well as assessing next-generation immunotherapeutics. By maintaining features of a patient's own tumor microenvironment, such patient-derived models are poised to meaningfully contribute to the functional assessment of individual tumors to provide a tailored approach to treatment. Among contemporary models, patient-derived organotypic tumor spheroids (PDOTS) have emerged as a promising microfluidic-based platform that is well positioned to become a useful tool for precision medicine efforts. The advantages and limitations of PDOTS and related state-of-the-art patient-derived tumor models, as well as ongoing challenges facing the clinical implementation of patient-derived tumor models, are reviewed.