**8. Oncolytic Viruses for the Treatment of Irreversible Hard Defects**

In cancers where there are genetic defects in the HLA pathway, attempts to mount a comprehensive adaptive immune response are likely to be futile. In these cancers (Figure 2, categories I–L), decisions over how best to invoke ICD or stimulate antigen presenting cells becomes straightforward because none are likely to be successful. For these cancers, the full spectrum of oncolytic mechanisms and arming strategies will need to focus on achieving cytotoxicity independent of HLA expression, and this embodies the essence of the whole concept of direct virolysis. Prior to discussing the range of different HLA-independent cytotoxic strategies available to oncolytic viruses, it is worth challenging the very notion that hard HLA defects are definitively irreversible. Oncolytic viruses have the capacity, in principle, to normalize HLA expression in any cell they infect.
