Table 2. Classification of type I ICD inducers determined by their major targets to provoke antitumor responses.
| Anticancer agents | Type of cell death induced | DAMPs | Major targets by ICD inducers | Preclinical observations for inciting antitumor immunity |
|---|---|---|---|---|
| Cytotoxic agents (mitoxantrone, oxaliplatin, anthracyclines) | Apoptosis, autophagic cell death, necroptosis | Ecto-CRT, ERp57, HMGB1, and ATP release | Nucleus (DNA or DNA-related proteins for cell mitosis) | In vivo antitumor effect is mitigated by depletion of CD8+T cells. Immunogenicity requires ecto-CRT in prophylactic tumor vaccination mouse models. |
| Cyclophosphamide (CTX) | Apoptosis | Ecto-CRT, HMGB1 release | Nucleus (DNA) | Metronomic doses of CTX deplete Treg from bed and tumors, CTX modulates DCs to produce IL-12 |
| Shikonin | Apoptosis, necroptosis | Ecto-CRT, ecto-Hsp70 | Cytosol (pyruvate kinase-M2 protein) | DCs incubated with shikonin increase Th1 cells but decrease Treg cells |
| Bortezomib | Apoptosis, autophagic cell death | Ecto-Hsp90 | Cytosol (26S proteasome) | Cytotoxicity of NK cells against bortezomib-treated cells increased |
| 7A7 (EGFR-specific antibody) | Apoptosis | Ecto-CRT, ERp57, ecto-Hsp70, ectp-Hsp90 | Cell surface receptor (EGFR) | Contribution of CD4+ T and CD8+ T to 7A7-triggered suppression of metastasis in mice model |
| Cardiac glycosides | Apoptosis | Ecto-CRT HMGB1 and ATP release | Cell surface (Na+/K+-ATPase, enzyme) | Prophylactic antitumor immunity is partially dependent on CD8+ T cells accompanied with Th17 cells |
| UVC irradiation | Apoptosis, necroptosis, necrosis | Ecto-CRT and ERp57, HMGB1 and ATP release | Nucleus (DNA) | UVC-treated cells increase susceptibility to attack by NK cells and total splenocytes |
| Vorinostat (HDAC inhibitor) | Apoptosis Autophagic cell death | Ecto-CRT | Nucleus (chromatin structure) | Promote the differentiation of CD8+ T cells to memory cells |
Abbreviations: Ecto-CRT, calreticulin exposure; DAMPs, damage-associated molecular patterns; ICD, immunogenic cell death, HMGB1; high-mobility group protein B1; Hsp, heat-shock protein; Treg, regulatory T cells; DCs, dendritic cells; IL-12, interleukin-12; NK, natural killer; EGFR, epidermal growth factor receptor; ATP, adenosine triphosphate; UVC, ultraviolet C