REVIEW article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Spatiotemporal Control of Immunogenic Cell Death: Rewiring Tumor-Immune Dialogues for Next-Generation Immunotherapy
Provisionally accepted
Chengbin Li1Lu Zhu1Yubing Wang1Lei Zhao1Xing Lin2Zhixian Sun1Tingxi Yan1Yingduo Wang1
JUNJIE PIAO1*Aihua Jin2*- 1Yanbian University, Yanji, China
- 2Yanbian University Hospital, Yanji, China
Select one of your emails
You have multiple emails registered with Frontiers:
Notify me on publication
Please enter your email address:
If you already have an account, please login
You don't have a Frontiers account ? You can register here
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.
Keywords: Cancer2, DAMPs4, immunogenic cell death1, immunotherapy3, TME5
Received: 10 Jan 2026; Accepted: 16 Feb 2026.
Copyright: © 2026 Li, Zhu, Wang, Zhao, Lin, Sun, Yan, Wang, PIAO and Jin. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
JUNJIE PIAO
Aihua Jin
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.