Actionable heterogeneity of hepatocellular carcinoma therapy-induced senescence

Therapy-induced senescence (TIS) is a stable cell cycle arrest in cancerous cells favoring immune control upon immune cell recruitment and activation via a senescence-associated secretory phenotype (SASP). Numerous studies have investigated the therapeutic applicability of TIS in hepatocellular carcinoma (HCC), a frequent cancer with high morbidity and mortality. Despite these efforts, a comprehensive understanding of how TIS may expose vulnerabilities specifically for immunotherapies, a potent means of cancer therapy, in HCC remains incomplete. Therefore, we conducted systematic studies to carefully characterize actionable and shared SASP- or other senescence-associated molecular parameters of TIS. We systematically compared the TIS inducers, etoposide and alisertib with a novel TIS inducer, CX5461, for their effects on SASP, surfaceome and innate immune clearance of representative human HCC cell lines. Surprisingly, all three compounds induced both metastasis surface antigens but also immunotherapeutically tractable antigens like CD95 (Fas), CD276 (B7-H3) and CD340 (Her2). This was verified in four representative HCC cell lines and publicly available datasets of HCC. Interestingly, alisertib, etoposide and CX5461 rendered senescent HCC vulnerable to be targeted by either T-cell-engaging bispecific antibodies or CAR NK cells. Collectively, our study indicates that heterogenous, but selective features of HCC senescence may be exploited by different immunotherapeutic approaches.

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Publication Details

Journal
Cancer Immunology Immunotherapy
Published
2025-05-15
DOI
https://doi.org/10.1007/s00262-025-04060-w
Citations
3
Primary Topic
Immunotherapy and Immune Responses
Type
article
Field-Weighted Citation Impact
2.39

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article

Actionable heterogeneity of hepatocellular carcinoma therapy-induced senescence

Caroline Schönfeld, Manfred Claassen, M. Schmidtke, Michael Schindler et al.
3 citations
Cancer Immunology Immunotherapy
Immunotherapy and Immune Responses
2.39
article

Actionable heterogeneity of hepatocellular carcinoma therapy-induced senescence

Caroline Schönfeld, Manfred Claassen, M. Schmidtke, Michael Schindler, Sepideh Babaei, Alexander N.R. Weber, Ana Tapia‐Abellán, Pujan Engels, K. Hebbel, Maria Mateo Tortola, Daniel Dauch, Sebastian Hörner, Georgios Vavouras Syrigos, András Szolek, Katharina Wolter, Sylwia A. Stefańczyk, Lars Zender, Min Zhou
article en
3 citations

Abstract

Therapy-induced senescence (TIS) is a stable cell cycle arrest in cancerous cells favoring immune control upon immune cell recruitment and activation via a senescence-associated secretory phenotype (SASP). Numerous studies have investigated the therapeutic applicability of TIS in hepatocellular carcinoma (HCC), a frequent cancer with high morbidity and mortality. Despite these efforts, a comprehensive understanding of how TIS may expose vulnerabilities specifically for immunotherapies, a potent means of cancer therapy, in HCC remains incomplete. Therefore, we conducted systematic studies to carefully characterize actionable and shared SASP- or other senescence-associated molecular parameters of TIS. We systematically compared the TIS inducers, etoposide and alisertib with a novel TIS inducer, CX5461, for their effects on SASP, surfaceome and innate immune clearance of representative human HCC cell lines. Surprisingly, all three compounds induced both metastasis surface antigens but also immunotherapeutically tractable antigens like CD95 (Fas), CD276 (B7-H3) and CD340 (Her2). This was verified in four representative HCC cell lines and publicly available datasets of HCC. Interestingly, alisertib, etoposide and CX5461 rendered senescent HCC vulnerable to be targeted by either T-cell-engaging bispecific antibodies or CAR NK cells. Collectively, our study indicates that heterogenous, but selective features of HCC senescence may be exploited by different immunotherapeutic approaches.

Cancer Immunology ImmunotherapyVol. 74(7)
German Cancer Research Center (DE), Heidelberg University (DE), Department of Virology (FR), German Center for Infection Research (DE), University Children's Hospital Tübingen (DE), Bernstein Center for Computational Neuroscience Tübingen (DE), Institute of Medical Microbiology and Hygiene (DE), Institute of Virology of the Slovak Academy of Sciences (SK), Deutsches Konsortium für Translationale Krebsforschung (DE), University of Tübingen (DE)
Deutsche Forschungsgemeinschaft, Volkswagen Foundation, Eberhard Karls Universität Tübingen, Universitätsklinikum Tübingen, Medizinischen Fakultät, Eberhard Karls Universität Tübingen, Chinese Government Scholarship
Good health and well-being
Openalex Percentile: Top 11%
Immunotherapy and Immune Responses
2.39
DOIOpen Access PDFOpenAlex
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