Calcium ion (Ca2+), a necessary element for human body, acts as important secondary message in cells and also plays critical roles in various cellular process and functions. The Ca2+ levels in human body and cells (extracellular and intracellular) are maintained in a physiological range, which refers as Ca2+ homeostasis. Depletion of Ca2+ inhibits cell growth while Ca2+ overload can cause cell death [1]. Targeting on the mitochondrial Ca2+ overload is proposed for tumor treatment by inducing cell death. In ovarian cancer cells, chrysophanol and morusin were shown to promote cell death and inhibit invasion by inducing mitochondrial Ca2+ overload [2,3]. In human triple-negative breast cancer cells, chetomin treatment can increase Ca2+ overload in the mitochondria, which promote caspase-3-mediated cell death [4]. In addition, the redistribution of Ca2+ between these Ca2+ store organelles, such as endoplasmic reticulum (ER), mitochondria and lysosome, also controls critical cellular function and process and has been highly attractive to screen novel anticancer drugs [5].

Nanomedicine has demonstrated significant advantages in tumor therapy and opened up a new road in the field of tumor therapy. Nanomedicine usually increases drug circulation time in the body, increases drug load, enhances drug stability, achieves drug enrichment in specific organs or tissues, and controls drug release, thereby improving the therapeutic effect. Early studies have showed Ca2+-based nanoparticles (NPs) have exhibited promising potential as gene/drug delivery and imaging for cancer therapy [[6], [7], [8]]. With the development of nanotechnology and molecular technology, one of the underlying mechanism of these effective Ca2+-based NPs was identified as their mediated Ca2+ overload [9,10].

Recently, a novel special cell death type was firstly defined as “calcicoptosis” due to Ca2+ overload by a Ca2+-based NPs. In this study, Bu and Liu's team constructed a pH-sensitive sodium-hyaluronate-modified calcium peroxide (SH–CaO2) NP to induce tumor cell death by Ca2+ overload [11]. In the acidic tumor microenvironment, the SH-CaO2 NPs were degraded and release H2O2 and free Ca2+. The increased H2O2 induced oxidative stress, and persistent elevation of Ca2+ level interfered the metabolic and proliferative processes, induced mitochondria and ER stress and thus caused cell death, and local Ca2+ enrichment also promoted the tumor calcification [11]. Given their capability to induce multiple cell death by targeting Ca2+ homeostasis, Ca2+-based nanomaterials have garnered significant interest for potential clinical applications.

In this review, we summarized the novel anticancer nanomaterials-induced multiple cell death types including apoptosis, autophagy, and pyroptosis due to Ca2+ overload in the tumor cells. We reviewed the roles of these anticancer nanomaterials on Ca2+ homeostasis, including transcellular Ca2+ influx and efflux, and intracellular Ca2+ change in the cytosolic and organelles, and combination of Ca2+ overload with other metal ions homeostasis. Therefore, our review provides an integrative discussion of the cell death types induced by these new anticancer therapy materials, which could deeply understand the underlying mechanism and enhance their efficiency and specificity. It enlightens to exploit calcium homeostasis disruption as an anti-cancer approach using nanotechnologies in the future.