Inflammatory microenvironment remodelling by tumour cells after radiotherapy

Area of Science:

• Oncology
• Immunology
• Radiotherapy

Background:

• Immune checkpoint inhibitors (ICIs) have transformed cancer therapy, but many patients do not respond.
• Resistance to ICIs necessitates novel combination strategies to improve treatment efficacy.
• Radiotherapy's immunomodulatory potential offers a promising combination partner for ICIs.

Purpose of the Study:

• To review the role of radiotherapy in enhancing ICI efficacy.
• To explore how DNA damage response (DDR) inhibitors can augment radiotherapy-ICI combinations.
• To highlight tumour cell-autonomous signalling pathways activated by radiotherapy.

Main Methods:

• Review of current research on radiotherapy and ICI combinations.
• Analysis of preclinical and clinical data on radiotherapy's immunomodulatory effects.
• Investigation of tumour cell-autonomous signalling, including DNA damage response (DDR) and cytosolic nucleic acid sensor pathways.

Main Results:

• Radiotherapy can convert immunologically 'cold' tumors to 'hot' by releasing pro-inflammatory mediators and increasing immune cell infiltration.
• Radiotherapy-induced tumour cell micronuclei activate pathways like cGAS-STING, remodeling the tumor immune microenvironment.
• Radiotherapy modulates neoantigen expression, impacting anti-tumour immunosurveillance.

Conclusions:

• Radiotherapy is a potent immunomodulator that can synergize with ICIs.
• Combining radiotherapy with DDR inhibitors may overcome ICI resistance by exploiting tumour cell-autonomous mechanisms.
• Targeting radiotherapy-induced signalling pathways presents a novel strategy to enhance cancer immunotherapy.