The Tumor Microenvironment (TME) has a key role in Solid Tumor Therapy Screening. The 3D TME-aligned model recapitulates original tumor microenvironment and promotes naïve behavior of tumor and immune cells. The pre-activation step of expanded autologous Tumor Infiltrate Lymphocytes (TILs) through incubation with bispecific antibodies potentializes tumor lysis driven by Immune Oncology (IO) Drugs. The cell retrieval at the end of treatment allows full mode of action characterization by FCM and description of genetic basis of resistance.