Immunogenic Cell Death (ICD) in Cancer Immunotherapy

Immunogenic cell death (ICD) represents a distinct form of strategy in oncology, where dying cancer cells are converted into stimuli that drive long-lasting antitumor immunity (i.e. a source of in situ immunization). Unlike non-immunogenic apoptosis, ICD elicits robust immune activation through the release of damage-associated molecular patterns (DAMPs). By promoting immune recognition of tumor antigens, ICD bridges cell death and immune activation, transforming non-immunogenic "cold" tumors into highly infiltrated "hot" tumors ^{[1] [2]}.

Mechanistically, ICD is initiated by endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) generation, which activate signaling cascades such as PERK/eIF2α/CHOP axis, resulting in type I interferon (IFN) responses and cytokine release (e.g., IL-1β, IFN-β, TNF-α). Key signs of ICD include: (1) calreticulin (CRT) exposure on the plasma membrane, (2) ATP secretion serving as chemoattractant, (3) HMGB1 release activating TLR4, and (4) uptake of dying or dead cells by dendritic cells (DCs) ^{[3] [4] [5]}.

Established ICD induction strategies can be broadly divided into chemical agents (e.g. chemical protein phosphatase 1/GADD34 inhibitors) and physical approaches. There are two main types of ICD inducers – type I inducers (e.g. Oxa) and type II inducers, including IrIII NHC and AuI complexes. Metal complexes, in particular, have emerged as potent ICD inducers due to their chemical modularity and ability to target multiple stress pathways simultaneously. Nanoparticle-based ICD delivery systems are also gaining attention for their high efficiency and reduced systemic toxicity. In various preclinical models, ICD signaling has been associated with superior responses to cancer therapy, such as anthracyline-based chemotherapy, anticancer agents targeting epidermal growth factor (EGFR), multitarget tyrosine kinase inhibitors and radiation therapy ^{[6] [7] [8]}.

Overall, harnessing and enhancing ICD holds great promise for transforming conventional cancer therapies into powerful, immune-driven treatment modalities.