Cisplatin and temozolomide combinatorial treatment triggers hypermutability and immune surveillance in experimental cancer models

  • Cancer Cell. 2025 Jul 14;43(7):1296-1312.e7. doi: 10.1016/j.ccell.2025.05.014.
Pietro Paolo Vitiello  1 ,  Benoit Rousseau  2 ,  Rosaria Chilà  3 ,  Paolo Battuello  1 ,  Vito Amodio  3 ,  Vittorio Battaglieri  1 ,  Gaia Grasso  4 ,  Sharon Scardellato  3 ,  Achille Anselmo  5 ,  Francesca Clemente  6 ,  Giuseppe Rospo  4 ,  Simona Lamba  4 ,  Alice Bartolini  7 ,  Federica Pisati  8 ,  Claudio Tripodo  9 ,  Noemi Congiusta  7 ,  Mariangela Russo  4 ,  Giovanni Crisafulli  3 ,  Federica Di Nicolantonio  10 ,  Giovanni Germano  11 ,  Luis A Diaz Jr  12 ,  Alberto Bardelli  13
Affiliations
  • 1. Department of Oncology, Molecular Biotechnology Center, University of Torino, 10126 Turin, Italy; IFOM ETS - The AIRC Institute of Molecular Oncology, 20139 Milan, Italy.
  • 2. Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 3. IFOM ETS - The AIRC Institute of Molecular Oncology, 20139 Milan, Italy.
  • 4. Department of Oncology, Molecular Biotechnology Center, University of Torino, 10126 Turin, Italy.
  • 5. Flow Cytometry Resource, Advanced Cytometry Technical Applications Laboratory (FRACTAL), IRCCS Ospedale San Raffaele, 20132 Milan, Italy; Università Vita-Salute San Raffaele, 20132 Milan, Italy.
  • 6. Flow Cytometry Resource, Advanced Cytometry Technical Applications Laboratory (FRACTAL), IRCCS Ospedale San Raffaele, 20132 Milan, Italy.
  • 7. Candiolo Cancer Institute, Fondazione del Piemonte per l'Oncologia (FPO) - IRCCS, 10060 Candiolo (TO), Italy.
  • 8. Histopathology Unit, Cogentech S.C.a.R.L., 20139 Milan, Italy.
  • 9. IFOM ETS - The AIRC Institute of Molecular Oncology, 20139 Milan, Italy; Histopathology Unit, Cogentech S.C.a.R.L., 20139 Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milano, 20122 Milan, Italy.
  • 10. Department of Oncology, Molecular Biotechnology Center, University of Torino, 10126 Turin, Italy; Candiolo Cancer Institute, Fondazione del Piemonte per l'Oncologia (FPO) - IRCCS, 10060 Candiolo (TO), Italy.
  • 11. IFOM ETS - The AIRC Institute of Molecular Oncology, 20139 Milan, Italy; Department of Medical Biotechnology and Translational Medicine, University of Milano, 20054 Milan, Italy. Electronic address: [email protected].
  • 12. Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: [email protected].
  • 13. Department of Oncology, Molecular Biotechnology Center, University of Torino, 10126 Turin, Italy; IFOM ETS - The AIRC Institute of Molecular Oncology, 20139 Milan, Italy. Electronic address: [email protected].
PMID: 40513578 DOI: 10.1016/j.ccell.2025.05.014
Abstract

Hypermutation induced by mismatch repair (MMR) inactivation leads to immune surveillance in colorectal Cancer (CRC) and in several Other malignancies. We investigated the impact of a rationally designed chemotherapy combination on the generation of hypermutation and immunogenicity in otherwise immune-refractory CRC and breast Cancer mouse models. Combinatorial treatment with cisplatin (CDDP) and temozolomide (TMZ) induces an adaptive downregulation of MMR, resulting in chemotherapy-dependent hypermutability and increase in predicted neoantigens. This combination specifically alters the immune fitness of the tumors, ultimately leading to CD8+ T cell-mediated immune surveillance, immunoediting of chemotherapy-induced neoantigens, and durable immunological memory. Treatment with CDDP and TMZ also remodels the innate immune microenvironment and induces long-lasting responses and complete rejections when combined with anti-PD-1 therapy in mice. The same effects are not observed using the clinically approved combination of 5-fluorouracil, oxaliplatin, and irinotecan (FOLFOXIRI). Treatment-induced hypermutation can enhance anti-tumor immune responses, offering additional avenues for Cancer treatment.

Keywords
chemotherapy; cisplatin; colorectal cancer; cytotoxic chemotherapy; immune checkpoint blockade; immune rewiring; immune surveillance; mismatch repair modulation; neoantigens; temozolomide.
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