Targeting the Notch1‐YY1‐ICAM1 Signaling Axis Enhances the Efficacy of Immunotherapy in HCC by Activating CD8 ⁺ T‐Cell‐Driven Cancer Cell Pyroptosis

Abstract Immunotherapy has shown a modest clinical benefit in advanced hepatocellular carcinoma (HCC), probably due to tumor immunosuppressive functions. Although Notch1 signaling has been implicated in tumor immune escape, its underlying mechanism is unclear. Here, Notch1 signaling is established as a determinant of immunotherapy efficacy in HCC. Studies showed that high Notch1 expression correlates with poor progression‐free survival and worse immunotherapeutic response in recurrent HCC patients, while Notch1 overexpression promotes cancer cell escape by inhibiting CD8 ⁺ T cell activation. Mechanistically, Notch1 overexpression upregulates the expression of transcriptional factor YY1 (Yin‐Yang 1), which in turn represses ICAM1 expression to prohibit CD8 ⁺ T cell‐derived granzyme‐driven cancer cell pyroptosis and cytotoxicity. Finally, co‐administration of a PD‐L1 antibody with PEI‐siYY1 represses HCC tumor growth without causing severe adverse effects, as observed with the Notch1 inhibitor DAPT. The results establish that targeting Notch1‐YY1‐ICAM1 signaling axis may enhance immunotherapy efficacy by activating CD8 ⁺ T cell‐driven cancer cell pyroptosis, providing a safe and effective treatment strategy for HCC patients.