2. Academic Validation
  3. Cisplatin and temozolomide combinatorial treatment triggers hypermutability and immune surveillance in experimental cancer models

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

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: giovanni.germano@unimi.it.
  • 12 Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: diazl5@mskcc.org.
  • 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: alberto.bardelli@unito.it.
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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