We describe herein a series of robust single-component Ca²⁺-selective ion channel or actuators tailored for remote control of Ca²⁺ signaling in mammals. Existing tools are either derived from engineered channelrhodopsin variants without strict Ca²⁺ selectivity or based on engineered GPCRs that might crosstalk with other signaling pathways. We introduce three different approaches to confer photosensitivity to STIM1 and ORAI as the two essential components for the calcium release-activated (CRAC) channel. These genetically-encoded calcium channels or actuators (GECAs) display biophysical features reminiscent of the ORAI1 channel, which enables precise optical control over Ca²⁺ signals and hallmark Ca²⁺-dependent physiological responses. GECAs can be further coupled with upconversion nanoparticles to enable wireless optogenetics in vivo. We demonstrate the use of GECAs to modulate anti-cancer immune response and intervene in neurodegeneration in a Drosophila model of amyloidosis. Similar approaches have been extended to photo-control immunogenic cell death (pyroptosis and necroptosis), as well as the design of photoswitchable chimera antigen receptor (CAR) T-cells for precision immunotherapy against both blood cancers and solid tumors.