Calcium ion-intervention therapy, predicated on the principle of intracellular Ca2+ overload, has emerged as a promising non-invasive strategy for oncological treatment. However, the precise delivery of Ca2+ to the tumor site and the effective modulation of Ca2+ influx is critical for enhancing the therapeutic effect of ionic interventions. Herein, we report the development of a novel endogenous hydrogen sulfide (H2S)-responsive nanoplatform, denoted as Ca2+@HKUST-1@PVP, which enables H2S-rapid responsive, targeted Ca2+ delivery, rapid ion release, and the synergistic modulation of calcium ion channels through photothermal and reactive oxygen species (ROS) mechanisms. The integration of HKUST-1 within the nanoplatform allows for selective reaction with tumor-associated H2S, triggering the rapid release of Ca2+ (around 80 % within two hours) and the concurrent generation of cooper sulfide (CuS) with near infrared (NIR) absorbance properties. These CuS serve a dual role as highly efficient photothermal agents and Fenton-like catalysts, which act in concert to modulate Ca2+ channels. The orchestrated cascade of events—encompassing rapid ion release, controllable photothermal effect and ROS-mediated modulation of Ca2+ influx—subverts the tumor’s calcium homeostasis and significantly amplifies the cytotoxic effects of calcium overload. Both in vitro and in vivo studies demonstrate that Ca2+@HKUST-1@PVP induces remarkable cytotoxicity and therapeutic efficacy through photothermal and ROS-enhanced calcium overload, surpassing the performance of HKUST-1 without Ca2+ loading. This study, therefore, presents a colon cancer-specific nanoplatform for photothermal and ROS synergistic ion-interference therapy, offering a novel avenue for the treatment of malignancies.