Phase separation of SMARCAL1 orchestrates epigenetic reprogramming and methionine metabolism to foster radioresistance and immunosuppression.

SMARCAL1 forms nuclear liquid-liquid phase separation condensates that increase histone H4 lactylation and chromatin accessibility, linked to radiotherapy resistance and immune therapy tolerance.

• Why it matters: The molecular basis for how phase separation drives pathological epigenetic and metabolic remodeling in therapy response is unclear, limiting biomarker and treatment strategies.
• What they did: The study shows SMARCAL1 condensates enhance histone H4 lactylation and chromatin accessibility, recruit DNA repair proteins, and regulate methionine adenosyltransferase transcription to promote the methionine cycle. It also identifies SMARCAL1 as a biomarker for predicting therapy response and stratifying patients, and uses digoxin to disrupt condensates.
• The result: Disrupting SMARCAL1 condensates with digoxin sensitizes tumours to radiotherapy and anti-PD1 therapy across multiple models, implying condensate-centered SMARCAL1-histone H4 remodeling supports radioimmunoresistance.

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