Radiation‐Induced Immunogenic Cell Death for Cancer Radioimmunotherapy

Abstract

In cancer treatment, traditional radiotherapy (RT) is routinely conducted in local tumors and limited by radioresistance, while recently emerged immunotherapy is confronted with low response rate, high cost, and cytokine release syndrome. Logically, the combination of the two therapeutic modalities into radioimmunotherapy is promising to complement with each other for systemic elimination of cancer cells with high specificity, efficiency, and safety. Especially, RT‐induced immunogenic cell death (ICD) plays an imperative role in radioimmunotherapy to evoke systemic immune response against cancer, including elevating the immunity of tumor antigens, recruiting and activating antigen‐presenting cells, and priming cytotoxic T lymphocytes for tumoral infiltration and cancer cell eradication. This review first retrospects the origin and concept of ICD, summarizes the major damage‐associated molecular patterns and signaling pathways, and highlights the characteristics of RT‐induced ICD. Subsequently, therapeutic strategies enhancing RT‐induced ICD for radioimmunotherapy are reviewed from the perspectives of enhancing RT itself, combination with other treatments, and stimulating the holistic immune system. On the basis of these published research and underlying mechanism, this work attempts to forecast possible directions for RT‐induced ICD enhancement to promote clinical applications.

Regulation of Ion Homeostasis for Enhanced Tumor Radio‐Immunotherapy

“…The inhibition of tumor growth depended not only on the enhanced radiotherapy, but was also attributed to the strengthened systemic antitumor immunotherapy, especially for the distant tumors. [ 20 ] First of all, radiotherapy could cause ICD of primary tumors and these nanoparticles promoted ICD of tumors, which was confirmed in in vitro experiments. Therefore, we carried out the immunofluorescence staining of frozen sections of the primary tumor for CRT, HSP‐70, and HSP‐90, which are considered as specific signaling molecules for ICD.…”

X‐Ray‐Induced Drug Release for Cancer Therapy

“…Emerging therapeutic strategies for cancer treatment utilizing X‐rays, such as X‐ray‐induced immunotherapy and boron neutron capture therapy (BNCT), have shown substantial effectiveness. X‐ray‐induced immunotherapy operates through two primary mechanisms: Firstly, radiotherapy can directly trigger immunogenic cell death, initiating innate and adaptive immune responses [87] . Secondly, when combined with checkpoint inhibitors, radiotherapy can induce abscopal effects, referring to radiotherapy‘s capacity to not only eradicate tumor cells in the irradiated region but also boost immune responses in distant non‐irradiated cells, facilitating more effective tumor treatment [88] .…”

“…X-ray-induced immunotherapy operates through two primary mechanisms: Firstly, radiotherapy can directly trigger immunogenic cell death, initiating innate and adaptive immune responses. [87] Secondly, when combined with checkpoint inhibitors, radiotherapy can induce abscopal effects, referring to radiotherapy's capacity to not only eradicate tumor cells in the irradiated region but also boost immune responses in distant non-irradiated cells, facilitating more effective tumor treatment. [88] However, the occurrence of abscopal effects is not always guaranteed, and the response rate can be low.…”

PREX2 contributes to radiation resistance by inhibiting radiotherapy-induced tumor immunogenicity via cGAS/STING/IFNs pathway in colorectal cancer

“…Radiation holds the potential to induce immunogenic cell death, enhancing radiosensitivity in tumor cells [28]. In Fig.…”