Abstract
<jats:p>Esophageal squamous cell carcinoma (ESCC) accounts for 90% of esophageal cancer cases worldwide and carries a poor prognosis, with overall survival below 20%. Chemotherapy remains the standard of care, yet acquired resistance is a critical barrier and the programs that establish and stabilize it are still poorly defined. Using an in vitro model of cisplatin resistance, we show that sustained platinum exposure does not drive a single, uniform resistant state but a continuum of adaptive transcriptional states. Most resistant clones presented a drug-tolerant persister (DTP)-like phenotype with stemness traits and slow-cycling behaviour. The DTP phenotype persisted after cisplatin withdrawal and was accompanied by markers of resistance, suggesting consolidation into a stable, acquired-resistance state. Unexpectedly, the effect of this reprogramming extended beyond cisplatin. Resistant clones displayed impaired cytostatic control and failed to suppress cell cycle programs upon CDK4/6 inhibition (CDK4/6i), revealing collateral cross-resistance. Multiomic profiling revealed an attenuation of the immune and inflammatory signaling expected from CDK4/6i, upregulation of immune-evasive markers and a dysregulated IFN pathway activation at baseline in cisplatin-resistant clones, reflecting an immune-evasive state consequent to cisplatin-induced reprogramming. A signature-based approach identified HDAC inhibitors as candidates for reversing resistance, and functional validation confirmed that HDACi combined with cisplatin fully restored parental-level sensitivity while also enhancing CDK4/6i efficacy, supporting epigenetic reprogramming as a strategy to counteract cross-resistance. Together, our findings define cisplatin resistance in ESCC as a reversible, epigenetically encoded and immune-evasive state, and provide a mechanistic rationale for HDACi-based combinations to restore sensitivity to both cisplatin and CDK4/6 inhibitors.</jats:p>