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Preprint WatchMildAugust 1st, 2026

Circulating Cell-Free Chromatin Particles Trigger a Unique Biphasic STING Signaling Program that Drives DNA Damage and Inflammation

Shabrish, S.; Patade, S.; Shinde, S.; Yelukar, R.; Raghuram, G. V.; Lopes, R.; Khare, N. K.; Mittra, I.

Circulating cell-free chromatin particles are internalised by peripheral blood mononuclear cells and trigger a biphasic STING signalling program, with an early trafficking and IRF3 or NF-kappaB phase preceding DNA damage and a later phosphorylation and cytokine phase; pharmacological inhibition or genetic deletion of STING attenuates both.

Mild contradiction

1 prior failure

One documented clinical failure (Phase 1 or 2) overlaps with the claimed mechanism.

The Claidex record holds one STING1 failure, the IMSA101 program closed on a sponsor decision in oligoprogressive solid tumours (imsa101-sting-agonist-immunesensor-shutdown). That program pushed STING agonism as an immune priming strategy. This preprint reports that endogenous chromatin particles already engage STING in circulating mononuclear cells and that the resulting program drives DNA damage and sustained inflammatory cytokine output, which implies a variable and patient specific baseline of pathway tone that agonist trials have generally not measured. If baseline STING engagement differs across patients according to circulating chromatin load, then a fixed agonist dose delivers different net pathway activity in different people, and the failure to see a consistent effect may reflect an unmeasured starting point rather than an inert mechanism.

Abstract excerpt

Cell death, DNA damage, and inflammation are closely interconnected processes implicated in ageing, cancer, and inflammatory disorders, yet the endogenous mechanisms linking them remain unclear. We previously identified cell-free chromatin particles (cfChPs), released from dying cells, as biologically active entities that enter neighboring cells and induce DNA damage and inflammation. Here, we show that serum-derived circulating cfChPs are rapidly internalized by human peripheral blood mononuclear cells and trigger a previously unrecognized biphasic STING signaling response. An early phase involves rapid STING trafficking to the perinuclear region and nucleus, with activation of IRF3 and NF-{kappa}B preceding detectable DNA damage. This is followed by a later phase characterized by STING phosphorylation, puncta formation, persistent DNA damage, and robust inflammatory cytokine production. Pharmacological inhibition or genetic deletion of STING markedly attenuated these responses. These findings identify extracellular cfChPs as endogenous DNA-damaging agents and reveal biphasic STING signaling as a mechanistic link between cell death, DNA damage, and sterile inflammation.

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1 of 1 indexed

This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.