Perturbing ion homeostasis has emerged as a novel therapeutic strategy for enhanced cancer therapy. Intensive development of ion homeostasis-disturbing agents has been investigated to activate cell death signaling pathways in cancer or to boost antitumor immunity in immune cells. These approaches can treat cancer via new mechanistic behaviors. Although the anticancer mechanism of ion homeostasis-disturbing agents is not yet clearly understood, a number of studies have recently been reported that demonstrate new possible mechanisms and their clinical applicability as novel anticancer agents. In this review paper, the authors elucidate various mechanisms for promoting cell death or activating antitumor immunity that are elicited using various ion homeostasis-perturbing agents. Moreover, the authors provide a perspective of the future that makes a bridge between ion homeostasis and cancer immunotherapy for future innovation.