CoREST complex (HDAC1-containing co-repressor complex)

Class

CoREST inhibitor

Pathway

Chromatin remodeling; reverses immune checkpoint inhibitor resistance associated with STK11 loss-of-function mutations

The CoREST complex is a multiprotein assembly built around the enzyme HDAC1 (histone deacetylase 1) together with LSD1 (a histone demethylase) and scaffolding proteins. It functions as a co-repressor, meaning it is recruited to specific genes and silences them by chemically modifying the histone proteins that package DNA, making chromatin more compact and less accessible to the transcription machinery. This silencing activity is used by cells to switch off genes that are not needed in a given context, but cancer cells can hijack it to suppress genes involved in immune recognition. This is particularly relevant in tumors carrying loss-of-function mutations in the STK11 gene, which tend to have an immune-suppressed microenvironment and often respond poorly to immune checkpoint inhibitors, a class of drugs that rely on functioning anti-tumor immune activity. By inhibiting the CoREST complex, it may be possible to reverse this repressive chromatin state, re-express immune-relevant genes, and restore sensitivity to checkpoint blockade in tumors that would otherwise resist it. This approach reflects a broader strategy of combining epigenetic modulation with immunotherapy to overcome specific, molecularly defined mechanisms of resistance.