According to the literature 24, only 46 cases of radiotherapy-mediated immune activation and subsequent abscopal effects were reported from 1969 to 2014, indicating the huge challenges as well as enormous room for improvement 25, 26, 27, 28. However, radiation-induced systemic immune responses are insufficient to meet clinical needs 23. These ICD-associated DAMPs could potentially promote the activation and migration of dendritic cells (DCs), which then prime T cells for systemic anti-tumor immune responses 22. Moreover, RT could increase ROS level in the ER, leading to calreticulin (CRT) exposure 21. ROS induced by RT could destroy the integrity of the nucleus and release high mobility group protein B1 (HMGB1) 4, 8. Extensive studies have confirmed that RT could activate the immune system by inducing ICD 19, 20. Owing to low systemic side effects and definite curative effects, about 50% of tumor patients would receive radiation therapy 18. Radiotherapy (RT) is a widely used tumor treatment that utilizes high-energy ionizing radiation to generate DNA damage in tumor cells 16, 17. Even after treatment with checkpoint blockade immunotherapies (CBI), including antibodies for cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and programmed-cell-death protein 1 (PD-1), most patients presented insufficient systemic immune responses for tumor regression 13, 14, 15. Unfortunately, in the clinic, many tumors are poorly immunogenic 9, and tumor cells could evade immune surveillance 10, 11, 12. The released or exposed DAMPs could mediate maturation and migration of dendritic cells (DCs), subsequently priming the anti-tumor adaptive immune responses 8. ICD could be induced by chemical (chemotherapies, etc.) 3, physical (ionizing radiation, photodynamic therapeutics, etc.) 4, 5 and infective (oncolytic virus, etc.) agents 6, which trigger intracellular stress including reactive oxygen species (ROS) and structural/functional alterations of the endoplasmic reticulum (ER), and the release of damage-associated molecular patterns (DAMPs) 7.
Immunogenic cell death (ICD) is a specific cell death modality to elicit an immune response against the antigens of dead or dying tumor cells 1, 2.
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