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Combining Notch signaling inhibition with immune checkpoint inhibitors (ICIs) provides a therapeutic rationale to overcome intrinsic ICI resistance in hepatocellular carcinoma, and exosomal analysis can serve as a non-invasive tool to stratify patients for this combined therapy. Novelty: ClaimNovelty.SYNTHESIS. Consensus alignment: ConsensusAlignment.NEUTRAL.

December 11, 2024Open Access

Notch Signaling and PD-1/PD-L1 Interaction in Hepatocellular Carcinoma: Potentialities of Combined Therapies

AMAnnapaola MontagnerUniversity of Bologna AAAndrea ArleoUniversity of Bologna FSFabrizia SuzziIstituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori

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Abstract

Immunotherapy has shown significant improvement in the survival of patients with hepatocellular carcinoma (HCC) compared to TKIs as first-line treatment. Unfortunately, approximately 30% of HCC exhibits intrinsic resistance to ICIs, making new therapeutic combinations urgently needed. The dysregulation of the Notch signaling pathway observed in HCC can affect immune cell response, reducing the efficacy of cancer immunotherapy. Here, we provide an overview of how Notch signaling regulates immune responses and present the therapeutic rationale for combining Notch signaling inhibition with ICIs to improve HCC treatment. Moreover, we propose using exosomes as non-invasive tools to assess Notch signaling activation in hepatic cancer cells, enabling accurate stratification of patients who can benefit from combined strategies.

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