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.

数十年的基础研究已经确定了 Ca ²⁺对各种 T 细胞功能的重要性，例如细胞毒性、增殖、分化和细胞因子分泌。我们现在对近端 TCR 信号如何启动 Ca ²⁺流入以及这种流入如何随后改变 T 细胞中的转录活动有了很好的理解。由于嵌合抗原受体（CAR）-T疗法在临床上取得了巨大成功，是否有可能利用Ca ²⁺信号进一步推进CAR-T研究？CAR 信号与 TCR 信号有何不同？如何以高通量方式识别功能性 CAR？各种Ca ^{2+ 的}定量CAR/TCR 激活下游的信号可能有助于回答这些问题。在这里，我们首先总结了最近使用 Ca ²⁺染料、基因编码的 Ca ²⁺指示剂 (GECI) 或转录活性报告基因来了解体外和体内CAR 激活的研究。我们接下来回顾了几个概念验证报告，这些报告通过光或超声操纵 Ca ²⁺信号，以实现对 T 细胞功能的精确时空控制。这些努力虽然是初步的，但为解决治疗性 T 细胞的靶向/非肿瘤问题开辟了新的途径。其他调节 Ca ^{2+ 的方式}还讨论了信号，例如无线电波和电脉冲。因此，监测或操纵T 细胞中的Ca ²⁺信号为我们提供了许多推进癌症免疫治疗的机会。