Ca2+ overload is caused by the abnormal accumulation of Ca2+, which is a potential therapeutic strategy for inhibiting tumor growth. However, due to the limited intracellular Ca2+ concentration, its anticancer effect is non-significant. Herein, near-infrared (NIR)-responsive nanoparticles NPs-PCa (DPPC-DSPE-PEG2000-NH2@PDPP@CaO2@DOX) were designed and prepared to achieve photothermal trigger of Ca2+ release, thereby increasing intracellular Ca2+ content. Furthermore, the nanoparticles convert light to heat to activate the transient receptor potential cation channel subfamily V member 1 (TRPV1) ion channels, allowing external Ca2+ to flow into the cells, further increasing the Ca2+ concentration. NPs-PCa nanoparticles overcome the limitation of insufficient concentration by increasing Ca2+ in both internal and external approaches. Meanwhile, an imbalance of intracellular Ca2+ induces mitochondrial dysfunction and ultimately results in cancer cell death. This study provides an effective strategy for inhibiting breast cancer tumor growth by regulating Ca2+ concentration.