Chimeric antigen receptor T cell and T cell receptor T cell therapies, commonly referred to as CAR-T and TCR-T therapies, are often characterized by their molecular design, including receptor affinity, antigen specificity, signaling domains, and markers associated with exhaustion. These parameters are clearly important, and they have driven much of the progress in the field. At the same time, the therapeutic success of these treatments depends on events that unfold at the level of direct physical cell-cell contacts. A therapeutic T cell must encounter a target cell, establish contact, interact and maintain engagement long enough to trigger a meaningful response. Whether this sequence occurs reliably is not determined by molecular features alone.

In practice, CAR-T and TCR-T cells display substantial heterogeneity in how they interact with target cells. Some contacts are stable and productive, leading to target cell killing and downstream immune activation. Others are brief, ineffective, or prematurely terminated. These differences can arise even among cells that appear similar based on conventional phenotypic or transcriptional profiling. Much of current analysis captures the aftermath of these interactions rather than the interactions themselves. Cytokine release, proliferation, exhaustion markers, or bulk cytotoxicity assays provide indirect evidence that engagement has occurred, but they offer limited insight into how that engagement unfolded. This gap becomes particularly relevant when trying to explain variability in therapeutic response. Two CAR-T cell therapy products may show comparable expansion and marker expression, yet differ markedly in clinical outcome. In such cases, differences in CAR-T cell interactions, including contact stability, frequency, or spatial organization within tissues, may play a decisive role.

Importantly, interaction “quality” is not determined by the therapeutic cell alone. Target cell properties, the surrounding cellular environment, and local inhibitory or supportive signals all shape cell communication. This makes interaction behavior an emergent property of the system rather than a fixed attribute of the engineered cell. From this perspective, improving CAR-T or TCR-T cell therapy is not only a matter of optimizing receptor design or intracellular signaling. It also involves understanding how these cells behave once they are embedded in a complex cellular context. Without direct insight into cell-cell interactions, attempts to rationally optimize therapies remain partly blind. Recognizing this does not invalidate existing analytical approaches. Marker-based profiling and functional assays remain essential. However, they may benefit from being complemented by measurements that capture interaction behavior more directly, particularly when therapies fail in ways that are difficult to explain post hoc.

CAR-T and TCR-T therapies thus provide a clear example of how interaction-level phenomena can shape therapeutic outcome. They illustrate why single-cell centric profiling, while necessary, may be insufficient to fully account for function. This highlights the need for novel technologies that can directly capture and characterize physical cell-cell interactions in a systematic manner and thereby help inform therapy decision and development.