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Cancer therapy

A cFLIP-flop switch for senolysis

Nature Cancer volume 3, pages 1279–1281 (2022)Cite this article

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Persistent senescent cancer cells have tumor-promoting potential, making their selective elimination a prime therapeutic objective. The death receptor inhibitor cFLIP has now been shown to counter the susceptibility of senescent cells to DR5-mediated extrinsic apoptosis, which can be therapeutically exploited.

Cellular senescence reflects a stable stress-inducible state switch that lastingly halts proliferation and hence operates as a tumor-suppressive mechanism1. However, the massive secretion of largely proinflammatory and often nuclear factor-κB (NF-κB)-driven cytokines, the senescence-associated secretory phenotype (SASP) and complex epigenetic remodeling that leads to stem-like cellular reprogramming, which drives aggressive tumor growth following occasional cell-cycle re-entry, underlie tumor-promoting features pertaining to the persistence of senescent cancer cells2. Therefore, therapeutic agents that blunt the SASP, called senomorphics, or that directly aim at eliminating persistent senescent cells, termed senolytics, have increasingly gained interest as an additional layer of anticancer treatment strategy3. This therapeutic concept was first demonstrated to be effective in chemotherapy-induced senescent lymphomas4. The idea of therapy-induced senescence (TIS) as a first hit, followed by a senolytic second hit, was later dubbed the ‘one–two punch’ concept5. In recent years, many drugs have been presented as senolytic candidates, including immune checkpoint inhibitors that unleash senescence-targeting T-cell immunity6. However, despite evidence in preclinical models and promising results from early phase clinical trials1,7, there is an ongoing need to identify additional targets and therapeutics as broad-spectrum effective senolytics across cancer entities.

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Fig. 1: The NF-κB-governed cFLIP-flop state switch between death and survival in TIS.

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Authors and Affiliations

  1. Medical Department of Hematology, Oncology and Tumor Immunology, Charité–Universitätsmedizin Berlin, Molekulares Krebsforschungszentrum, Berlin, Germany

    Dorothy N. Y. Fan & Clemens A. Schmitt

  2. Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany

    Clemens A. Schmitt

  3. Johannes Kepler University, Linz, Austria

    Clemens A. Schmitt

  4. Department of Hematology and Oncology, Kepler University Hospital, Linz, Austria

    Clemens A. Schmitt

  5. Deutsches Konsortium für Translationale Krebsforschung, Berlin, Germany

    Clemens A. Schmitt

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  1. Dorothy N. Y. Fan
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  2. Clemens A. Schmitt
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Correspondence to Clemens A. Schmitt.

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Fan, D.N.Y., Schmitt, C.A. A cFLIP-flop switch for senolysis. Nat Cancer 3, 1279–1281 (2022). https://doi.org/10.1038/s43018-022-00455-1

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