Bioengineering strategies for off-the-shelf, cell-based cancer immunotherapy

Cancer immunotherapy has reshaped modern oncology by leveraging immune effector cells to recognize and eliminate malignant tissues. Among cell-based approaches, adoptive cell therapies, most prominently chimeric antigen receptor (CAR) T cells, have produced high response rates and deep remissions in several hematologic malignancies. Despite these clinical successes, broad deployment remains limited by the dominant autologous manufacturing paradigm, which is associated with high per patient cost, prolonged vein to vein time, and heterogeneity in starting material and final product quality, particularly in heavily pretreated patients. Off-the-shelf strategies aim to improve scalability and access by standardizing either the cellular input, such as donor derived or renewable sources, or the engineering reagent used to program immune cells. Here, we review bioengineering approaches enabling three complementary off-the-shelf platforms, including allogeneic CAR T cells, natural killer and invariant natural killer T cell-based therapies, and in vivo CAR generation. Lastly, we outline the clinical translation outlook for off-the-shelf cell therapy, highlighting current limitations and future bioengineering and manufacturing directions. Together, these approaches highlight convergent design principles that will shape the next generation of broadly accessible cell-based cancer immunotherapies, including immune compatibility, controllable activation, and manufacturability.