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Updated: Jun 6, 2025

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RIPK1 inhibition in malignant cells potentiates immunotherapy and radiotherapy outcome

Jonathan G Pol1,2, Andrea Checcoli1,2,3, Manuela Lizarralde-Guerrero1,2,4

  • 1Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris Cité, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France.

Oncoimmunology
|November 25, 2024
PubMed

Insights

A novel small molecule inhibitor targets receptor-interacting serine/threonine-protein kinase 1 (RIPK1) for cancer therapy. This RIPK1 inhibitor enhanced the effectiveness of radiotherapy and immunotherapies in preclinical models.

Area of Science:

  • Molecular Biology
  • Immunology
  • Oncology

Background:

  • Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a key regulator of cell death pathways, including apoptosis and necroptosis.
  • RIPK1 also mediates pro-inflammatory nuclear factor-kappa B (NF-κB)-dependent signaling.
  • Dysregulation of these pathways is implicated in cancer development and progression.

Purpose of the Study:

  • To investigate a novel small molecule that induces the proteolytic degradation of RIPK1.
  • To evaluate the therapeutic potential of this RIPK1 inhibitor in preclinical cancer models.

Main Methods:

  • Development of a small molecule inhibitor targeting RIPK1.
  • Preclinical testing of the RIPK1 inhibitor in combination with standard cancer treatments.

Main Results:

  • The small molecule effectively induced RIPK1 degradation.
  • Combination therapy with the RIPK1 inhibitor significantly improved anticancer efficacy.
  • Enhanced responses were observed with radiotherapy, PD-1 blockade immunotherapy, and CTLA-4 blockade radioimmunotherapy.

Conclusions:

  • Targeting RIPK1 degradation represents a promising strategy for cancer treatment.
  • RIPK1 inhibition can overcome resistance and enhance the efficacy of existing anticancer therapies.
Keywords:
Cancer immunotherapyimmune checkpoint inhibitorimmunogenic cell deathnecroptosisradiotherapy

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