Therapeutic targeting of cell death-immune crosstalk in cancer to rewire the tumor immune microenvironment

The immune system plays a central role in anticancer defense by coordinating antitumor responses that inhibit the initiation, progression, and metastasis of malignancies. Emerging evidence underscores the crucial interplay between regulated cell death (RCD) pathways and immune activation, particularly immunogenic cell death (ICD). ICD refers to a specific form of regulated cell death in which tumor cells undergo death and release damage-associated molecular patterns (DAMPs) and other signaling molecules, thereby reshaping the tumor immune microenvironment (TIME). While the canonical RCD pathways are well-established, the inducers of ICD, the spatiotemporal regulation of TIME dynamics, and the functional states of immune cells remain incompletely understood. We thoroughly evaluated contemporary therapeutic approaches that exploit the mechanisms of RCD-driven immunomodulatory effects, including strategies to potentiate ICD and amplify antitumor immune responses. The novelty of this review lies in its dual perspective: delineating how tumor-intrinsic death programs reprogram the tumor TIME and how immune-cell death directly dictates its polarization toward immunostimulatory versus immunosuppressive states, ultimately shaping therapeutic outcomes. We analyzed in depth how different forms of RCD shape antigen presentation, guide immune cell infiltration, and affect checkpoint signaling, underscoring their dual potential to support or hinder antitumor responses. Furthermore, we summarized the current landscape of ICD-inducing interventions, including chemotherapy, radiotherapy, oncolytic viruses, tumor vaccines, and nanotechnology-based platforms, underscoring their potential to convert immunologically "cold" tumors into "hot" ones and to synergize with immune checkpoint blockade. In addition, we highlighted promising combination strategies aimed at directly modulating immune cell death pathways to sustain effector cell function and overcome exhaustion, offering novel insights for the development of next-generation precision immunotherapies. By delineating the crosstalk between tumor/immune cell death pathways, this study provides a roadmap for developing precise immunotherapies that exploit RCD-TIME interactions to overcome treatment resistance.