"Immunotherapy is a highly effective treatment for advanced cancer, but patient responses are dichotomous, resulting in either durable remission or minimal clinical benefit. Although immune checkpoint blockade enhances T cell cytotoxicity, tumor cells frequently create exclusionary tumor microenvironments that suppress antitumor immunity. While tumor cell-intrinsic features that promote immune-permissive microenvironments in immunotherapy responders are well characterized, there are currently no therapies that directly target tumor cells to convert exclusionary microenvironments into permissive ones.
Chromatin remodelers are compelling candidates for such strategies because they can induce stable phenotypic reprogramming by restructuring 3D chromatin architecture and modulating multiple transcription factor networks. Moreover, their enzymatic, ATPase-dependent nucleosome remodeling activity makes them attractive drug targets. By mining melanoma patient datasets, we identified the chromatin remodeler CHD7 as progressively upregulated during cancer progression and inversely associated with immune-permissive tumor microenvironments and immunotherapy response.
We found that CHD7 directly represses immunomodulatory interferon signaling in melanoma cells, and CHD7 inhibition sensitizes melanoma cells to T cell-mediated cytotoxicity in vitro and enhances in vivo T cell infiltration and immunotherapy response. Together, these findings identify CHD7 as a mechanistic, first-in-class example of a CHD-family chromatin remodeler that directly regulates tumor–immune interactions and nominate CHD7 as a potential therapeutic target to render tumors more responsive to immunotherapy."