Interferon-independent STING enforces epithelial genome-integrity checkpoint to restrain tumor evolution

Xiang Hang; Martina Macino; Clemens Woitaske-Proske; Nicholas Bodenstein; J P Bernardes; Florian Tran; Nicole A Schmid; Gabriela Rios Martini; Felix Wottawa; J Bornhaeuser; Nassim Kakavand; Oliver Dyck Dionisi; Silke van den Bossche; Guang Yang; Qicong Wu; Julia Kugler; Lina Welz; Björn Konukiewitz; Julius Clemens Fischer; Christian Peifer; Stefan Schreiber; Philip C Rosenstiel; Markus Tschurtschenthaler; Ashley D. Sanders; Konrad Aden

doi:10.64898/2026.02.17.706442

Cancer BiologybioRxivMar 25, 2026

Preprint

Interferon-independent STING enforces epithelial genome-integrity checkpoint to restrain tumor evolution

Xiang Hang iD, Martina Macino iD, Clemens Woitaske-Proske iD, Nicholas Bodenstein, J P Bernardes, Florian Tran iD, Nicole A Schmid iD, Gabriela Rios Martini, Felix Wottawa iD, J Bornhaeuser, Nassim Kakavand iD, Oliver Dyck Dionisi iD, Silke van den Bossche, Guang Yang iD, Qicong Wu, Julia Kugler, Lina Welz iD, Björn Konukiewitz iD, Julius Clemens Fischer iD, Christian Peifer iD, Stefan Schreiber iD, Philip C Rosenstiel iD, Markus Tschurtschenthaler iD, Ashley D. Sanders iD, Konrad Aden iD

Abstract

STING is canonically known for mediating interferon responses to cytosolic DNA, yet its cell-intrinsic role in genome maintenance beyond the immune context is unknown. Here we show that epithelial STING functions as a type I interferon-independent genome-integrity checkpoint. STING loss impairs homologous recombination repair, attenuates ATM-associated damage signaling, elevates CDK1 activity, and causes chromosomal instability revealed by single-cell Strand-seq, culminating in spontaneous intestinal adenocarcinoma. These defects arise before tumor formation and confer selective vulnerability to CDK inhibition in tumor organoids and human colorectal cancer cells. Our findings identify STING as a cell-autonomous guardian of epithelial genome stability that restrains chromosomal instability-driven tumor evolution beyond its canonical immune function.

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