Mutations in oncogenes, tumour-suppressor genes and microRNA genes can lead to cancer development. Although in most cases cancer is a predisposition of somatic mutations, mutations in germ-line can also cause a heritable or familial cancer (Croce, 2008). In 2000, Hanahan and Weinberg introduced six hallmarks of cancer, which are factors that allow cancer cells to survive, proliferate, and distribute. These hallmarks include sustaining proliferative signalling, evading growth suppressors, activating invasions and metastasis, enabling replicative immortality, inducing angiogenesis, and resisting cell death (Hanahan & Weinberg, 2000). In 2011, reprogramming energy metabolism and evading immune destruction were added to their first proposition of cancer hallmarks (Hanahan & Robert, 2011), and in 2022 non-mutational epigenetic reprogramming, unlocking phenotype plasticity, senescent cells and polymorphic microbiomes were added as additional hallmarks reflecting the importance of both, the tumour cells and the tumour microenvironment (Hanahan, 2022).

The term “immunosurveillance”, a hypothesis that the immune system can recognise and eliminate developing cancer was first suggested by Frank MacFarlane Burnet and Lewis Thomas (Burnet, 1957, Thomas, 1959). In 2001, Shankaran et al. proposed the term “immunoediting” by showing that the immune system in strong interaction like a “struggle of life” with tumour cells and that primary tumours with decreased immunogenicity can develop when escaping immune recognition and elimination (Shankaran et al., 2001). Dunn et al. introduced the “three Es” as the three phases in cancer immunoediting: elimination, equilibrium and escape (Dunn, Old, & Schreiber, 2004). Elimination refers to the previously-known immunosurveillance, where tumour cells are recognised and killed by the immune system. Equilibrium is the phase of latency after incomplete tumour destruction in the elimination phase, whilst escape applies to the out-growth of tumours that have surpassed the immunological control. The latter tumours are the ones which are then diagnosed and require treatment. Furthermore, the generation of an immunosuppressive microenvironment is also beneficial for tumours to escape immune invasion (Murphy & Weaver, 2017). In the review of Vesely et al., they discussed how cancer immunoediting can be manipulated to induce an anti-tumour response by targeting specific immune molecules in a specific immunoediting stage (Vesely, Kershaw, Schreiber, & Smyth, 2011). Considering this, it is important to understand how the immune system responds to tumours to benefit from it in improving cancer patients’ survival.

According to the world health organisation (WHO), there were approximately 19.3 million new cancer cases, with female breast cancer as the most frequently diagnosed cancer (approximately 2.3 million new cases) recorded worldwide in 2020. On average, approx. 60% of these cancer patients receive RT during the course of their disease for either curative purposes (curative RT) or to control the symptoms (palliative RT) (Spencer, Parrish, Barton, & Henry, 2018). However, RT alone in most cases can stop proliferation of the tumour cells and kill them, but cannot induce robust local and systemic anti-tumour immune responses. Therefore, combinations of RT with immunotherapies (ITs) to take advantage of immunomodulatory properties of RT are widely researched. Multimodal cancer therapies consisting of RT and ITs to either boost the immune response or dampen immunosuppression have shown promising results in pre-clinical and in recent clinical studies. Immune checkpoint inhibitors (ICIs), which are involved in enhancing anti-tumour responses by inhibiting immune tolerance are the most common IT used to combine with RT (Zhang, Liu, Chen, & Yu, 2022). In this chapter, we will discuss how the immune system interacts with cancer cells, how this interaction is modulated by RT, and the resulting impact on the development of RT and immunotherapy combinations.