Spatiotemporal Control of Immunogenic Cell Death: Rewiring Tumor-Immune Dialogues for Next-Generation Immunotherapy

Abstract

Immunogenic cell death (ICD) is a regulated cell death process distinguished by its ability to stimulate an adaptive immune response. This occurs through the emission of damage-associated molecular patterns (DAMPs), such as calreticulin (CRT), adenosine triphosphate (ATP), High Mobility Group Box 1 (HMGB1), type I interferons (IFN-α/β), and heat shock proteins(HSPs). Collectively, these signals promote dendritic cells (DCs) maturation, facilitate antigen cross-presentation, and trigger cytotoxic T lymphocytes (CTLs) activation. This cascade of immunostimulatory events is critical for converting immunologically "cold" tumors into "hot" ones. This review systematically explains the molecular mechanism of ICD, focusing on the space-time regulation of DAMPs emission and their role in remodeling the tumor immune environment. We also list a variety of ICD inducers, including conventional chemotherapeutic drugs, targeted drugs, nanotechnology-driven systems, physical means , and tumor-lytic viruses. The core theme is the synergistic potential of ICD with immune checkpoint inhibitors(ICIs), chimeric antigen receptor T cells (CAR-T cells)therapy, and microbiome regulation, supported by emerging preclinical and clinical evidence. We also discuss some current challenges, such as the heterogeneity of tumors released by DAMPs and immune escape mechanisms, and explore the development of biomarkers for patient stratification. In the future, we have emphasized some promising research directions, including artificial intelligence-assisted drug design, spatially differentiated metometric technology, and engineered immune cell therapy to achieve precise space-time-induced immune cell death. This review presents the mechanistic insights and transformative research directions for positioning ICD as a central pillar in the future landscape of immuno-oncology.