Cell Therapies and Bispecific Engagers: Redefining Strategies against Checkpoint Resistance

Most patients with solid tumors either never benefit from immune checkpoint inhibitors (ICIs) or relapse after an initial response, underscoring the need for additional therapies. Clinical and translational evidence points to two complementary strategies to overcome ICI resistance: redirection of effector cells by imposing novel tumor-specificity via engineered T cell receptors (TCRs), chimeric antigen receptors (CARs), and CD3/TCR engagers, and augmentation of endogenous responses by tumor infiltrating lymphocyte (TIL) therapy, cytokine support, and microenvironment remodeling. This review integrates emerging signals across platforms and examines why some designs succeed while others stall. Therapeutic efficacy depends on tumor target features and the surrounding microenvironment. Clinical efficacy is emerging when (i) tumor targets show high density and uniformity with restriction to malignant cells, (ii) antigen presentation can be harnessed for TCR-based strategies or bypassed with CARs and engagers, and (iii) the tumor contexture is permissive or convertible with regional delivery and stromal, vascular, or myeloid modulation. Engineering solutions such as tuned costimulation, cytokine armoring, and resistance to suppression improve effector expansion and persistence. Safe and scalable delivery requires exposure control and operational solutions in manufacturing and logistics. Step-up dosing and optimized routes can limit peak exposure and resource intensity. Autologous manufacturing and time to treatment remain limiting, whereas off-the-shelf platforms improve logistics. For patients, near-term progress will rely on biomarker-guided selection and pragmatic trials that address sequencing and bridging, while benchmarking durability across modalities.