Advances in nanotherapeutics for tumor treatment by targeting calcium overload

Traditional antitumor strategies are facing challenges such as low therapeutic efficacy and high side effects, highlighting the significance of developing non-toxic or low-toxic alternative therapies. As a second messenger, calcium ion (Ca²⁺) plays an important role in cellular metabolism and communication. However, persistent Ca²⁺ overload leads to mitochondrial structural and functional dysfunction and ultimately induced apoptosis. Therefore, an antitumor strategy based on calcium overload is a promising alternative. Here, we first reviewed the classification of calcium-based nanoparticles (NPs) for exogenous Ca²⁺ overload, including calcium carbonate (CaCO₃), calcium phosphate (CaP), calcium peroxide (CaO₂), and hydroxyapatite (HA), calcium hydroxide, etc. Next, the current endogenous Ca²⁺ overload strategies were summarized, including regulation of Ca²⁺ channels, destruction of membrane integrity, induction of abnormal intracellular acidity and oxidative stress. Due to the specificity of the tumor microenvironment, it is difficult to completely suppress tumor development with monotherapy. Therefore, we reviewed the progress based on mitochondrial Ca²⁺ overload, which improved the treatment efficiency by combining photothermal therapy (PTT), photodynamic therapy (PDT), chemodynamic therapy (CDT), sonodynamic therapy (SDT), immunogenic cell death (ICD) and gas therapy. We further explored in detail the advantages and promising new targets of this combination antitumor strategies to better address future opportunities and challenges.