De Rosis Salvatore, Monaco Gianni, Hu Joyce, Hett Erick, Lappano Rosamaria, Marincola Francesco M, Asadi Ali, Maggiolini Marcello
Department of Pharmacy and Health and Nutritional Sciences, University of Calabria, Rende, 87036, Italy.
Translational and Advance Medicine (TAM) Biosciences, Nashville, TN, USA.
J Transl Med. 2025 Jul 22;23(1):808. doi: 10.1186/s12967-025-06839-y.
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.
癌细胞精心调控周围的肿瘤微环境（TME），以在为其提供营养的组织再生与由免疫原性警报信号引发的组织破坏之间达成微妙平衡。在稳态下，这种脆弱的平衡有利于癌症生长。然而，旨在增强癌细胞免疫原性或反应性免疫应答的疗法能够使平衡逆转，从而清除宿主体内的癌症。由于高通量技术的进步，揭示了以前未知领域中被称为“暗物质”的新生物学特性，对影响这种平衡的因素的理解正在迅速发展。这些进展对于理解导致免疫介导的癌症排斥的真正机制至关重要。本综述聚焦于癌症的遗传、表观遗传和代谢紊乱，这些紊乱类似于细胞内病原体感染所引起的情况，这种现象被称为“病毒模拟”（VM）以及过去未被探索的癌症/宿主细胞相互作用的其他方面，这些方面增强了VM效应。在癌症方面，VM促使癌细胞代谢发生改变，导致产生被宿主免疫系统识别为外来物质的异常细胞产物。后者被定义为“暗物质”，以强调这些模糊的生物产物对TME所产生的强大影响，就如同大量不可见粒子能够决定星系的旋转周期一样。另一方面，众多以前未被重视的因素会影响宿主反应。因此，在这里我们提出对暗物质的扩展定义，其范围超出癌细胞内在生物学的局限，涵盖影响TME内细胞网络的各种因素，给出更宽泛的解释。
