Amplifying Ca²⁺ overload by engineered biomaterials for synergistic cancer therapy

Ca²⁺ overload is one of the most widely causes of inducing apoptosis, pyroptosis, immunogenic cell death, autophagy, paraptosis, necroptosis, and calcification of tumor cells, and has become the most valuable therapeutic strategy in the field of cancer treatment. Nevertheless, several challenges remain in translating Ca²⁺ overload-mediated therapeutic strategies into clinical applications, such as the precise control of Ca²⁺ dynamics, specificity of Ca²⁺ homeostasis dysregulation, as well as comprehensive mechanisms of Ca²⁺ regulation. Given this, we comprehensively reviewed the Ca²⁺-driven intracellular signaling pathways and the application of Ca²⁺-based biomaterials (such as CaCO₃-, CaP-, CaO₂-, CaSi-, CaF₂-, and CaH₂-) in mediating cancer diagnosis, treatment, and immunotherapy. Meanwhile, the latest researches on Ca²⁺ overload-mediated therapeutic strategies, as well as those combined with multiple-model therapies in mediating cancer immunotherapy are further highlighted. More importantly, the critical challenges and the future prospects of the Ca²⁺ overload-mediated therapeutic strategies are also discussed. By consolidating recent findings and identifying future research directions, this review aimed to advance the field of oncology therapy and contribute to the development of more effective and targeted treatment modalities.