Abstract: Generation and identification of highly effective immune effector cell in terms of target cell-killing activity can be enhanced by optimizing the proximity between a target cell and the immune effector cell. The cancer-killing T cells described herein can provide highly effective therapies for diverse cancer types, e.g., solid cancers, hematological cancers, and metastatic forms thereof. Provided herein are ex-vivo methods of generating cancer-killing T cells, compositions comprising such immune cells; methods of using the cells, methods of selecting optimal agents for enhancing the target cell killing activity, methods of selecting an optimized immune cell and methods of using this approach to evaluate patient responsiveness to other cancer therapies.