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Aneuploid cancers inactivate Stat1 to circumvent immune surveillance

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Aneuploid cancer cells inactivate Stat1 signaling as a specific mechanism to evade immune surveillance and prevent immune-mediated elimination of chromosomally unstable cells. This immune evasion strategy is essential for aneuploid cells to overcome the cellular fitness costs of aneuploidy-induced stress and establish tumors in vivo. [@schubert_cancer_2021]

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Aneuploid cancers, characterized by abnormal chromosome numbers, face increased immune cell infiltration as a consequence of chromosomal instability, which creates immunogenic signals that would normally limit tumor growth through immune surveillance. To overcome this fitness cost, aneuploid tumors have evolved a conserved mechanism involving the dual inactivation of Stat1 signaling combined with increased Myc activity, which specifically suppresses the immune infiltration induced by chromosomal instability and allows aneuploid cells to evade detection and persist despite aneuploidy-induced stress. This Stat1 inactivation pathway is conserved between mouse and human aneuploid cancers, representing a shared evolutionary solution distinct from more general tumor suppressor loss like p53 inactivation, which is common across cancers but not specifically enriched in chromosomally unstable tumors. While the mechanistic relationship between chromosomal instability, immune infiltration, and Stat1/Myc alterations is established, questions remain about the precise molecular signals generated by aneuploidy that trigger immune recognition and how the heterogeneity of chromosomal changes across tumor subclones influences the selective pressure for these immune evasion mechanisms.

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