<p>Disrupting calcium ions (Ca²⁺) homeostasis to induce calcium overloading has emerged as a promising strategy for cancer therapy. However, calcium overloading based on exogenous calcium salts (such as calcium carbonate and calcium peroxide) can easily lead to off-target Ca²⁺ release, causing severe side effects such as hypercalcemia and cardiac or renal dysfunction. This review explores the calcium-free nanomaterials for mediating targeted calcium dysregulation in tumors. These nanomaterials function not by carrying Ca²⁺ but by precisely regulating endogenous calcium signaling pathways. They promote massive Ca²⁺ influx through targeted activation of calcium channels and/or inhibit Ca²⁺ efflux by suppressing pumps, effectively triggering intracellular calcium accumulation. Such a strategy efficiently induces mitochondrial dysfunction, endoplasmic reticulum stress, and immunogenic cell death, thereby inhibiting tumor growth and metastasis while potentiating antitumor immunity. We systematically summarize the design principles, mechanisms of action, and therapeutic applications of these calcium-free nanoplatforms, highlighting their potential to overcome the limitations of traditional therapies and boost ion-interference-based cancer treatment.</p>