Abstract
Summary: Regulatory T cells (Tregs) maintain immune homeostasis but also constrain antitumor immunity. Here, we show that the DNA sensor AIM2 sustains immunosuppressive programs in Tregs and limits responses to immune checkpoint blockade. Using an MC38 colorectal cancer model, Treg specific deletion of AIM2 enhanced the efficacy of PD1 blockade. This effect was associated with reduced effector Tregs and immunosuppressive myeloid populations, alongside increased cytotoxic activity of CD8 T cells. AIM2 deficient Tregs exhibited diminished suppressive programs and enhanced interferon responsive signatures, accompanied by broad remodeling of tumor immune interactions. These findings identify AIM2 as a key regulator of Treg mediated immune suppression and suggest that targeting AIM2 may improve the efficacy of cancer immunotherapy.