Cancer is a highly heterogeneous disease, thus a “one-size-fits-all” treatment approach has not been effective in cancer management. Interactions between tumor and their environment at the cellular and systemic levels have been shown to contribute to variability in therapy outcomes. Tumor cells interact at the cellular level with immune cells and tumor associated fibroblasts to modulate tumor cell susceptibility to various treatment modalities. At the systemic level, anti-cancer drugs can cause differential toxic side effects to other tissues, which limits the maximum tolerable dose for patients. While patient derived xenografts (PDx) are being explored as mouse avatars for pre-clinical screening of an optimal personalized therapeutic regime, animal models are expansive and not scalable for screening applications. To fill this technological gap, we have developed Patient-Derived Micro-Avatar Chips (PD-MAC), which integrate the biological diverse characteristics of patient-derived tumor cells and high configurability of microfluidic systems, to study tumor-environment interactions at the cellular and systemic level. A 3D microenvironment can be engineered using micropillar structures to support the formation and remodeling of patient-derived parental and metastatic oral squamous cell carcinoma (OSCC) into 3D micro-tumors (PD-mTs). We have developed a modular approach to achieve system integration with various microfluidic components such as micro-pumps and valves, and a second tissue chip to facilitate the scaling of the PD-MAC to study systemic effects of chemotherapeutic drugs. Finally, we demonstrate the manipulation of parental and metastatic OSCC tumor and immune (NK) cells using hydrodynamic trapping arrays to investigate differential immune-mediated cytotoxicity.