TY  - JOUR
AU  - Engels, Pujan
AU  - Szolek, Andras
AU  - Hörner, Sebastian
AU  - Syrigos, Georgios Vavouras
AU  - Hebbel, Kim
AU  - Schmidtke, Michelle
AU  - Zhou, Min
AU  - Mateo-Tortola, Maria
AU  - Schönfeld, Caroline
AU  - Stefanczyk, Sylwia
AU  - Wolter, Katharina
AU  - Babaei, Sepideh
AU  - Schindler, Michael
AU  - Claassen, Manfred
AU  - Dauch, Daniel
AU  - Zender, Lars
AU  - Tapía-Abellán, Ana
AU  - Weber, Alexander
TI  - Actionable heterogeneity of hepatocellular carcinoma therapy-induced senescence.
JO  - Cancer immunology immunotherapy
VL  - 74
IS  - 7
SN  - 0340-7004
CY  - Heidelberg
PB  - Springer
M1  - DKFZ-2025-01018
SP  - 207
PY  - 2025
AB  - 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.
KW  - Humans
KW  - Carcinoma, Hepatocellular: pathology
KW  - Carcinoma, Hepatocellular: immunology
KW  - Carcinoma, Hepatocellular: drug therapy
KW  - Carcinoma, Hepatocellular: therapy
KW  - Liver Neoplasms: pathology
KW  - Liver Neoplasms: immunology
KW  - Liver Neoplasms: drug therapy
KW  - Liver Neoplasms: therapy
KW  - Cellular Senescence: drug effects
KW  - Pyrimidines: pharmacology
KW  - Cell Line, Tumor
KW  - Etoposide: pharmacology
KW  - Azepines: pharmacology
KW  - Senescence-Associated Secretory Phenotype: drug effects
KW  - Immunotherapy: methods
KW  - Hepatocellular carcinoma (Other)
KW  - Immunology (Other)
KW  - Immunotherapy (Other)
KW  - Senescence (Other)
KW  - Pyrimidines (NLM Chemicals)
KW  - MLN 8237 (NLM Chemicals)
KW  - Etoposide (NLM Chemicals)
KW  - Azepines (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40374812
C2  - pmc:PMC12081809
DO  - DOI:10.1007/s00262-025-04060-w
UR  - https://inrepo02.dkfz.de/record/301476
ER  -