Exploiting Ca²⁺ signaling in T cells to advance cancer immunotherapy

Decades of basic research has established the importance of Ca²⁺ to various T cell functions, such as cytotoxicity, proliferation, differentiation and cytokine secretion. We now have a good understanding of how proximal TCR signaling initiates Ca²⁺ influx and how this influx subsequently changes transcriptional activities in T cells. As chimeric antigen receptor (CAR)-T therapy has achieved great clinical success, is it possible to harness Ca²⁺ signaling to further advance CAR-T research? How is CAR signaling different from TCR signaling? How can functional CARs be identified in a high-throughput way? Quantification of various Ca²⁺ signals downstream of CAR/TCR activation might help answer these questions. Here we first summarized recent studies that used Ca²⁺ dye, genetically-encoded Ca²⁺ indicators (GECI) or transcriptional activity reporters to understand CAR activation in vitro and in vivo. We next reviewed several proof-of-concept reports that manipulate Ca²⁺ signaling by light or ultrasound to achieve precise spatiotemporal control of T cell functions. These efforts, though preliminary, opened up new avenues to solve the on-target/off-tumor problem of therapeutic T cells. Other modalities to regulate Ca²⁺ signaling, such as radio wave and electrical pulse, were also discussed. Thus, monitoring or manipulating Ca²⁺ signaling in T cells provides us many opportunities to advance cancer immunotherapy.