Single high-dose irradiation-induced iRhom2 upregulation promotes macrophage antitumor activity through cGAS/STING signaling

Purpose

The clinical application of stereotactic body radiotherapy (SBRT) allows a high dose
of radiation to be safely delivered to extracranial targets within the body; however,
a high dose per fraction(hypofractionation) have opened up the radiation oncology
field to new questions on a variety of dose-fractionation schedules, especially the
immunomodulatory effects of radiotherapy, which can change following various dose-fractionation
schedules. Herein we investigate the immunomodulatory effects of different fractionation
schedules.

Methods and materials

We established subcutaneous tumor model in WT C57BL/6J mice and STING-deficient mice.
And compared the tumor control efficacy of three different fractionation schedules:
2 Gy × 8, 4.5 Gy × 3, and 10 Gy × 1, which are similar biologically effective doses
(BEDs).

Results

We found the fractionation schedule of 10 Gy × 1 had a significantly higher antitumor
effect, suggesting that a single high dose induced enhanced antitumor immunity compared
to conventional fractionation (2 Gy × 8) and moderate hypofractionation (4.5 Gy × 3).
However, in STING-deficient mice, differential tumor control was not observed among
the three dose-fractionation schedules, suggesting that cGAS/STING signaling is involved
in the antitumor immune effects of single high-dose schedules. Mechanistically, we
found that conventional fractionation induced apoptosis; by comparison, single high-dose
was more attuned to induced necroptosis, leading to the release of intracellular irradiation-induced
dsDNA due to the loss of plasma membrane integrity, which then activated the dsDNA
sensing signaling cGAS/STING in the recruited macrophage. Furthermore, iRhom2, a member
of the conserved family of inhibitory rhomboid-like pseudoproteases, was upregulated
in infiltrated macrophages in the single high-dose irradiation microenvironment. Therefore,
iRhom2 positively regulates STING and directly promotes TNF-α secretion, this exacerbates
necroptosis of irradiated tumor cells, leading to continuous dsDNA release and enhancement
of cGAS/STING signaling antitumor immunity in a positive feedback loop.

Conclusions

iRhom2 amplifies antitumor signaling in a positive feedback loop mediated by cGAS/STING
signaling and TNF-driven necroptosis following single high-dose radiation.

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