Precision Epigenetic Reprogramming: CoREST Inhibition Sensitizes STK11-Mutant Tumors to Immune Checkpoint Blockade Therapy

Loss-of-function mutations in STK11 (also known as LKB1) define a molecular subtype of non-small cell lung cancer that is resistant to immune checkpoint blockade therapy, partially owing to impaired T-cell infiltration and suppressed antigen presentation. Emerging evidence implicates epigenetic deregulation as a key driver of immune evasion in STK11-mutant tumors. In this issue of Cancer Research, Ahronian and colleagues identified the CoREST complex, via histone deacetylase 1, as a vulnerability that can be targeted pharmacologically to restore immune sensitivity in STK11-mutant tumors. The authors developed TNG260, a selective small-molecule CoREST inhibitor with favorable pharmacologic properties and reduced toxicity relative to pan-histone deacetylase inhibitors. In preclinical models of STK11-deficient non-small cell lung cancer, TNG260 reprograms the tumor epigenome to upregulate immune genes and synergizes with anti-PD-1 therapy to induce durable tumor regressions. Early clinical data from an ongoing trial (NCT05887492) show increased histone acetylation and CD8+ T-cell infiltration in patient tumors treated with TNG260 and pembrolizumab. This commentary places these findings in the broader context of epigenetic modulation of antitumor immune response. We also outline key questions for future investigation, including durability of immune response, tumor-type specificity, and biomarker strategies for patient selection and response monitoring. See related article by Ahronian et al., p. 3966.