The dark matter in cancer immunology: beyond the visible- unveiling multiomics pathways to breakthrough therapies.

Cancer cells orchestrate the surrounding tumor microenvironment (TME) to strike a fine balance between tissue regeneration providing them with nutrients, and tissue destruction triggered by immunogenic alarm signals. At steady state, the tenuous balance favors cancer growth. Therapies aimed at enhancing the immunogenic properties of cancer cells or the reacting immune responses can, however, revert the equilibrium to clear the host of cancer. The understanding of factors that affect this balance is progressing rapidly due to advances in high throughput technologies disclosing from previously uncharted territories new biologies referred to as "dark matter". These advances are critical for the understanding of the true mechanisms leading to immune-mediated cancer rejection.This review focuses on cancer genetic, epigenetic and metabolic derangements that approximate those caused by intra-cellular pathogen infection, a phenomenon referred to as "viral mimicry" (VM) and other aspects of cancer/host cells interactions unexplored in the past that enhance the VM effects. On the cancer side, VM prompts alterations of cancer cell metabolism leading to the generation of aberrant cellular products recognized as foreign by the host's immune system. The latter are defined as "dark matter" to emphasize the powerful effects exerted by these obscure bioproducts on the TME as the mass of invisible particles can dictate the rotational period of galaxies. On the other side, a myriad of previously unappreciated factors can influence the host responses. Thus, here we propose an extended definition of dark matter beyond the limits of cancer cell-intrinsic biology, to a broader interpretation encompassing elements that influence the cellular networks within the TME.