Mitochondrial priming in therapy-induced senescence implications for CAR-TNK immunosenolytic therapy

Therapy-induced senescence (TIS) generates an immunogenic state in cancer cells by altering how they present antigens, produce cytokines, and organize their surfaceome. TIS can be exploited for therapeutic purposes using immunosenolytic strategies, including adoptive cellular therapies such as chime...

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Autores: Menendez, J.A., Lupu, R., Martin-Castillo, B., Sardanes, JOSEP, Alarcon, Tomas, Verdura, S., Cuyàs, E.
Tipo de recurso: artículo
Fecha de publicación:2025
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2072/489134
Acceso en línea:http://hdl.handle.net/2072/489134
Access Level:acceso abierto
Palabra clave:CAR-T cells
CAR-NK cells
mitochondria
BH3 mimetics
BH3 profiling
51
id ES_2d45dced2a22a85a3aafb5eadefdb884
oai_identifier_str oai:recercat.cat:2072/489134
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv Mitochondrial priming in therapy-induced senescence implications for CAR-TNK immunosenolytic therapy
title Mitochondrial priming in therapy-induced senescence implications for CAR-TNK immunosenolytic therapy
spellingShingle Mitochondrial priming in therapy-induced senescence implications for CAR-TNK immunosenolytic therapy
Menendez, J.A.
CAR-T cells
CAR-NK cells
mitochondria
BH3 mimetics
BH3 profiling
51
title_short Mitochondrial priming in therapy-induced senescence implications for CAR-TNK immunosenolytic therapy
title_full Mitochondrial priming in therapy-induced senescence implications for CAR-TNK immunosenolytic therapy
title_fullStr Mitochondrial priming in therapy-induced senescence implications for CAR-TNK immunosenolytic therapy
title_full_unstemmed Mitochondrial priming in therapy-induced senescence implications for CAR-TNK immunosenolytic therapy
title_sort Mitochondrial priming in therapy-induced senescence implications for CAR-TNK immunosenolytic therapy
dc.creator.none.fl_str_mv Menendez, J.A.
Lupu, R.
Martin-Castillo, B.
Sardanes, JOSEP
Alarcon, Tomas
Verdura, S.
Cuyàs, E.
author Menendez, J.A.
author_facet Menendez, J.A.
Lupu, R.
Martin-Castillo, B.
Sardanes, JOSEP
Alarcon, Tomas
Verdura, S.
Cuyàs, E.
author_role author
author2 Lupu, R.
Martin-Castillo, B.
Sardanes, JOSEP
Alarcon, Tomas
Verdura, S.
Cuyàs, E.
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv CAR-T cells
CAR-NK cells
mitochondria
BH3 mimetics
BH3 profiling
51
topic CAR-T cells
CAR-NK cells
mitochondria
BH3 mimetics
BH3 profiling
51
description Therapy-induced senescence (TIS) generates an immunogenic state in cancer cells by altering how they present antigens, produce cytokines, and organize their surfaceome. TIS can be exploited for therapeutic purposes using immunosenolytic strategies, including adoptive cellular therapies such as chimeric antigen receptor (CAR)-engineered T and natural killer (NK) cells. A frequently overlooked barrier may limit the success of these living drugs: mitochondrial apoptotic priming in the target TIS cancer cells. Contrary to the prevailing dogma, recent assessments of mitochondrial apoptotic signaling via BH3 profiling (a functional assay measuring proximity to the mitochondrial apoptotic threshold and identifying BCL-2 family dependencies) have revealed that TIS cancer cells are globally less primed for apoptosis than their proliferating precursors. TIS cancer cells exhibit a conserved, druggable dependence on specific members of the BCL-2 family for survival. Interestingly, the pre-existing priming and anti-apoptotic addictions of parental, non-senescent cells, are retained upon induction of senescence. This suggests an inherited mitochondrial memory that may predict the (immuno)senolytic responsiveness of TIS cancer cells. BH3 profiling could help to personalize CAR-based immunosenolytic therapy according to apoptotic readiness across pre- and post-TIS states. This companion diagnostic could inform the rational use of BH3 mimetics in combination with CARs and guide the engineering of precision immunosenolytic interventions such as armored CAR-T/NK cells neutralizing specific anti-apoptotic dependencies at the effector-target interface. This perspective reframes mitochondria as predictive checkpoints that can be monitored and targeted to enable TIS cancer cells to respond precisely and durably to adoptive CAR-T/NK immunotherapy within one-two punch senogenic-immunosenolytic designs.
publishDate 2025
dc.date.none.fl_str_mv 2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/2072/489134
url http://hdl.handle.net/2072/489134
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Frontiers in Immunology
dc.rights.none.fl_str_mv Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 21 p.
application/pdf
dc.publisher.none.fl_str_mv Frontiers Media
publisher.none.fl_str_mv Frontiers Media
dc.source.none.fl_str_mv RECERCAT (Dipòsit de la Recerca de Catalunya)
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869405304130633728
spelling Mitochondrial priming in therapy-induced senescence implications for CAR-TNK immunosenolytic therapyMenendez, J.A.Lupu, R.Martin-Castillo, B.Sardanes, JOSEPAlarcon, TomasVerdura, S.Cuyàs, E.CAR-T cellsCAR-NK cellsmitochondriaBH3 mimeticsBH3 profiling51Therapy-induced senescence (TIS) generates an immunogenic state in cancer cells by altering how they present antigens, produce cytokines, and organize their surfaceome. TIS can be exploited for therapeutic purposes using immunosenolytic strategies, including adoptive cellular therapies such as chimeric antigen receptor (CAR)-engineered T and natural killer (NK) cells. A frequently overlooked barrier may limit the success of these living drugs: mitochondrial apoptotic priming in the target TIS cancer cells. Contrary to the prevailing dogma, recent assessments of mitochondrial apoptotic signaling via BH3 profiling (a functional assay measuring proximity to the mitochondrial apoptotic threshold and identifying BCL-2 family dependencies) have revealed that TIS cancer cells are globally less primed for apoptosis than their proliferating precursors. TIS cancer cells exhibit a conserved, druggable dependence on specific members of the BCL-2 family for survival. Interestingly, the pre-existing priming and anti-apoptotic addictions of parental, non-senescent cells, are retained upon induction of senescence. This suggests an inherited mitochondrial memory that may predict the (immuno)senolytic responsiveness of TIS cancer cells. BH3 profiling could help to personalize CAR-based immunosenolytic therapy according to apoptotic readiness across pre- and post-TIS states. This companion diagnostic could inform the rational use of BH3 mimetics in combination with CARs and guide the engineering of precision immunosenolytic interventions such as armored CAR-T/NK cells neutralizing specific anti-apoptotic dependencies at the effector-target interface. This perspective reframes mitochondria as predictive checkpoints that can be monitored and targeted to enable TIS cancer cells to respond precisely and durably to adoptive CAR-T/NK immunotherapy within one-two punch senogenic-immunosenolytic designs.The work in the JM laboratory is supported by the Ministerio de Ciencia e Innovacion and the Spanish Research Agency (MCIN/AEI, grant PID2022-141955OB-I00, Plan Nacional de I+D+i, funded by MCIN/AEI/10.13039/501100011033/FEDER/UE ERDF A way of making Europe funded by the European Regional Development Fund), and the Emerging Research Group SGR 2021 01507 of the Agencia de Gestio d'Ajuts Universitaris i de Recerca (AGAUR, Generalitat de Catalunya) to BM-C. EC holds a Miguel Servet research contract (CP20/00003) from the Instituto de Salud Carlos III (Spain) and is supported by the grant PI22/00297 (Instituto de Salud Carlos III, Proyectos de I+D+I en Salud, Accion Estrategica en Salud 2021-2023, funded by the ERDF A way of making Europe). TA is grateful to the Isaac Newton Institute for Mathematical Sciences for support and hospitality during the program Mathematics of movement: an interdisciplinary approach to mutual challenges in animal ecology and cell biology during the final stages of this work under the EPSRC grant number EP/R014604/1. JS and TA have been funded by grant PID2021-127896OB-I00 funded by MCIN/AEI/10.13039/501100011033 ERDF A way of making Europe. This work has been funded also by the Spanish Research Agency (AEI) through the Severo Ochoa and Maria de Maeztu Program for Centers and Units of Excellence in R&D (CEX2020-001084-M). JM, JS, TA, and EC thank the CERCA Program/Generalitat de Catalunya for the institutional support.info:eu-repo/semantics/publishedVersionFrontiers Media2025info:eu-repo/semantics/article21 p.application/pdfhttp://hdl.handle.net/2072/489134RECERCAT (Dipòsit de la Recerca de Catalunya)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésFrontiers in ImmunologyAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:recercat.cat:2072/4891342026-05-29T05:05:01Z
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