Expanding Immunotherapy Beyond CAR T Cells: Engineering Diverse Immune Cells to Target Solid Tumors

Abstract

Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of certain hematologic malignancies, yet its success in solid tumors has been limited by antigen heterogeneity, an immunosuppressive tumor microenvironment, and barriers to cell trafficking and persistence. To expand the reach of cellular immunotherapy, multiple immune cell types—γδ T cells, invariant NKT cells, virus-specific T cells, natural killer (ΝΚ) cells, and myeloid effectors such as macrophages and dendritic cells—are now being explored as alternative or complementary CAR platforms. Each lineage brings unique advantages, such as the innate cytotoxicity and safety profile of CAR NK cells, the tissue infiltration and microenvironment-modulating capacity of CAR macrophages, or the MHC-independent recognition offered by γδ T cells. Recent advances in pharmacological strategies, synthetic biology, and artificial intelligence provide additional opportunities to overcome barriers and optimize CAR design and manufacturing scale-up. Here, we review the state of the art in engineering diverse immune cells for solid tumor therapy, highlight safety considerations across autologous, allogeneic, and in vivo CAR cell therapy approaches, and provide our perspective on which platforms might best address current unmet clinical needs. Collectively, these developments lay the foundation for next-generation strategies to achieve durable immunotherapy responses in solid tumors.