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Peer-reviewedCC BY 4.0Frontiers in Immunology

Reprogramming the tumor microenvironment in mesothelioma: from immune suppression to therapeutic opportunity

  • Luigi Cerbone1,2
  • Alessia Garau1,3
  • Andrea Balossino4
  • Simona Martinotti5,6
  • Elia Ranzato5,6
  • Carlo Genova7,8
  • Valentina Rigo9
  • Stefano Meda10
  • Silvia Ravera11
  • Hector Josè Soto Parra12
  • Maria Carmela Piccirillo13
  • Alessandra Gurrera14
5 more authors
  • Alberto Terminella15
  • Mattia Manitto16
  • Michela Croce9
  • Simona Coco4
  • Federica Grosso1
16 affiliations
  1. 1SSD Mesotelioma, Melanoma e Tumori Rari, IRCCS AOU SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy.
  2. 2DISSTE - Dipartimento per lo Sviluppo Sostenibile e la Transizione Ecologica, Università del Piemonte Orientale, Vercelli, Italy.
  3. 3SC Infrastruttura Ricerca Formazione e Innovazione, Dipartimento Attività Integrate Ricerca e Innovazione (DAIRI), IRCCS AOU SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy.
  4. 4UO Tumori Polmonari, Oncologia Medica, AOM - IRCCS Ospedale Policlinico San Martino, Genova, Italy.
  5. 5DiSIT- Dipartimento di Scienze e Innovazione Tecnologica, Università del Piemonte Orientale, Alessandria, Italy.
  6. 6SSD Laboratori di Ricerca, Dipartimento Attività Integrate Ricerca e Innovazione (DAIRI), IRCCS AOU SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy.
  7. 7UOC Clinica di Oncologia Medica, AOM - IRCCS Ospedale Policlinico San Martino, Genova, Italy.
  8. 8DIMI - Dipartimento di Medicina Interna e Specialità Mediche, Università degli Studi di Genova, Genova, Italy.
  9. 9UOC Bioterapie, AOM - IRCCS Ospedale Policlinico San Martino, Genova, Italy.
  10. 10SC Chirurgia Toracica, IRCCS AOU SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy.
  11. 11SC Malattie Apparato Respiratorio, IRCCS AOU SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy.
  12. 12UO Oncologia Medica, Azienda Ospedaliero Universitaria Policlinico "G. Rodolico-S. Marco", Catania, Italy.
  13. 13SC Sperimentazioni Cliniche, Istituto Nazionale Tumori IRCCS - Fondazione G. Pascale, Napoli, Italy.
  14. 14UOC Anatomia Patologica, Azienda Ospedaliero Universitaria Policlinico "G. Rodolico-S.Marco", Catania, Italy.
  15. 15UOC Chirurgia Toracica, Azienda Ospedaliero Universitaria Policlinico "G.Rodolico-S. Marco", Catania, Italy.
  16. 16SC Chirurgia Toracica, AOM - IRCCS Ospedale Policlinico San Martino, Genova, Italy.
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Abstract

Pleural mesothelioma (PM) is a rare and aggressive cancer with limited treatment options and poor prognosis. Unlike other thoracic cancers responding well to immunotherapy, PM typically lacks key predictive biomarkers such as Programmed Death-Ligand 1 (PD-L1) tumor expression. Nonetheless, immune checkpoint inhibitors (ICIs) have shown clinical activity in PM, particularly in non-epithelioid subtypes. However, only a subset of patients benefits from this approach, and resistance remains a major challenge. A growing body of evidence suggests that tumor microenvironment (TME) plays a central role in shaping this resistance. In PM, the TME is notably immunosuppressive, dominated by regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages. These elements act as a shield against immune activation, limiting the efficacy of ICIs. Novel therapeutic strategies aimed at depleting or modulating suppressive immune populations within the TME are emerging as promising avenues to overcome resistance and enhance the effectiveness of ICIs. In this narrative review, we examine the unique features of the TME in PM, its role in immunotherapy resistance, and emerging strategies aimed at harnessing or remodeling the TME to improve patient outcomes.

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Cite

BibTeXRIS
BibTeX
@article{cerbone2026reprogramming,
  title = {{Reprogramming the tumor microenvironment in mesothelioma: from immune suppression to therapeutic opportunity}},
  author = {Luigi Cerbone and Alessia Garau and Andrea Balossino and Simona Martinotti and Elia Ranzato and Carlo Genova and Valentina Rigo and Stefano Meda and Silvia Ravera and Hector Josè Soto Parra and Maria Carmela Piccirillo and Alessandra Gurrera and Alberto Terminella and Mattia Manitto and Michela Croce and Simona Coco and Federica Grosso},
  journal = {Frontiers in Immunology},
  year = {2026},
  month = oct,
  doi = {10.3389/fimmu.2026.1814514},
  url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1814514/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Reprogramming the tumor microenvironment in mesothelioma: from immune suppression to therapeutic opportunity
AU  - Luigi Cerbone
AU  - Alessia Garau
AU  - Andrea Balossino
AU  - Simona Martinotti
AU  - Elia Ranzato
AU  - Carlo Genova
AU  - Valentina Rigo
AU  - Stefano Meda
AU  - Silvia Ravera
AU  - Hector Josè Soto Parra
AU  - Maria Carmela Piccirillo
AU  - Alessandra Gurrera
AU  - Alberto Terminella
AU  - Mattia Manitto
AU  - Michela Croce
AU  - Simona Coco
AU  - Federica Grosso
PY  - 2026
DA  - 2026/10/06
JO  - Frontiers in Immunology
DO  - 10.3389/fimmu.2026.1814514
UR  - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1814514/full
AB  - Pleural mesothelioma (PM) is a rare and aggressive cancer with limited treatment options and poor prognosis. Unlike other thoracic cancers responding well to immunotherapy, PM typically lacks key predictive biomarkers such as Programmed Death-Ligand 1 (PD-L1) tumor expression. Nonetheless, immune checkpoint inhibitors (ICIs) have shown clinical activity in PM, particularly in non-epithelioid subtypes. However, only a subset of patients benefits from this approach, and resistance remains a major challenge. A growing body of evidence suggests that tumor microenvironment (TME) plays a central role in shaping this resistance. In PM, the TME is notably immunosuppressive, dominated by regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages. These elements act as a shield against immune activation, limiting the efficacy of ICIs. Novel therapeutic strategies aimed at depleting or modulating suppressive immune populations within the TME are emerging as promising avenues to overcome resistance and enhance the effectiveness of ICIs. In this narrative review, we examine the unique features of the TME in PM, its role in immunotherapy resistance, and emerging strategies aimed at harnessing or remodeling the TME to improve patient outcomes.
SN  - 1664-3224
ER  -