Inhibition of O-GlcNAc transferase activates type I interferon-dependent antitumor immunity by bridging cGAS-STING pathway

Reviewer #1 (Public Review):

Summary:

This study provides the detailed molecular mechanism of how OGT, an O-GlcNac transferase, promotes cancer progression. Using loss-of-function OGT models, the authors demonstrated that OGT cleaves HCF-1, an important guardian of genomic stability. The resulting genomic instability in OGT-knockout tumors leads to cytosolic DNA accumulation, the activation of cGAS-mediated type I IFN responses, and increased CD8+ T cell infiltration into the tumors. Moreover, treatment with OGT inhibitor synergized with anti-PDL1 immune-checkpoint blockade.

Strengths:

Novel findings of how OGT promotes tumor progression.

Weaknesses:

(1) Some of the data is problematic and does not always support the authors' conclusions.
(2) The writing needs significant improvement. In places, it is hard to understand or could mislead the readers.
(3) Figure legends are minimalistic and do not provide sufficient information.
(4) Discussion does not put the findings of this study into a broader context of the field but merely restates them.

Reviewer #2 (Public Review):

Summary:

In this study, the author demonstrates that deficiency or pharmacological inhibition of O-glcNac transferase (OGT) enhances tumor immunity in colorectal cancer models. The authors propose that OGT deficiency triggers a DNA damage response, activating the cGAS-STING innate immunity pathway and promoting a Type I interferon response. They suggest that OGT-mediated processing of HSF1 is crucial in maintaining genomic integrity. This research is significant as it identifies OGT inhibition as a potential immunomodulatory target in cancer treatment.

Strengths:

The strength of the paper lies primarily in the in vivo data, demonstrating the impact of OGT deficiency or inhibition on modulating tumor growth and anti-tumor immunity. The experiments are well-controlled. However, there are several unresolved questions:

Weaknesses:

The mechanisms of how OGT deficiency can trigger DNA damage and the role of this response in promoting immunity are only partially addressed in the manuscript.