Checkpoint-checkpoint combinations in cancer: from mechanistic rationale to translational impact.
8 affiliations
- 1Operative Research Unit of Medical Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, via Alvaro del Portillo 200, 00128, Rome, Italy.
- 2Research Unit of Medical Oncology, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, via Alvaro del Portillo 21, 00128, Rome, Italy.
- 3Department of Medical Oncology, U.O. Oncologia Medica 2, IRCCS Ospedale Policlinico San Martino, Genova, Italy.
- 4Department of Melanoma, Cancer Immunotherapy and Development Therapeutics - Istituto Nazionale Tumori IRCCS Fondazione "G. Pascale", Napoli, Italy.
- 5Operative Research Unit of Medical Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, via Alvaro del Portillo 200, 00128, Rome, Italy. [email protected].
- 6Research Unit of Medical Oncology, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, via Alvaro del Portillo 21, 00128, Rome, Italy. [email protected].
- 7Department of Surgery and Cancer, Hammersmith Hospital Campus, Imperial College London, London, UK. [email protected].
- 8Department of Neuroscience, Reproductive and Dental Sciences, Università degli Studi di Napoli "Federico II", Napoli, Italy.
Abstract
Background
Immune checkpoint inhibitors have reshaped the treatment of several cancers, producing durable responses in a subset of patients. However, most individuals either fail to respond or eventually develop resistance. Tumor immune escape results from heterogeneous and often overlapping mechanisms, including impaired antigen presentation, limited T-cell infiltration, co-expression of multiple inhibitory receptors, and suppressive tumor microenvironmental signals. These limitations have driven the development of combination strategies aimed at restoring more effective and sustained antitumor immunity.Main body
Among combination approaches, dual immune checkpoint blockade represents the most established strategy. The combination of CTLA-4 and PD-1 inhibitors targets complementary phases of the immune response: early T-cell priming in lymphoid organs and effector function within the tumor microenvironment. Long-term clinical data across melanoma, lung cancer, renal cell carcinoma, mesothelioma, and hepatocellular carcinoma support the ability of this approach to induce durable survival in a meaningful proportion of patients, albeit with increased immune-related toxicity. Building on this foundation, next-generation checkpoint combinations aim to counteract adaptive resistance and T-cell exhaustion. In particular, LAG-3, TIM-3, and TIGIT are frequently co-expressed with programmed death-1 on dysfunctional T cells. Emerging checkpoints such as VISTA, B7-H3, and BTLA further expand the landscape, particularly by modulating myeloid-driven suppression and advanced T-cell dysfunction. In parallel, bispecific antibodies integrating dual checkpoint targeting within a single molecule may enhance coordinated pathway inhibition and tumor localization.Conclusion
Immune checkpoint-based combinations represent an evolving strategy of immune restoration. Future advances will depend on biologically informed trial design, dynamic biomarkers, and rational optimization of dose and sequencing to maximize durable benefit while maintaining acceptable toxicity.
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BibTeX
@article{mazzocca2026checkpointcheckpoint,
title = {{Checkpoint-checkpoint combinations in cancer: from mechanistic rationale to translational impact.}},
author = {Alessandro Mazzocca and Silvia Calagna and Emanuele Claudio Mingo and Silvia Cavaliere and Michele Iuliani and Agostina Lagodin D'Amato and Luigi Scarpato and Francesco Pantano and Giuseppe Tonini and Bruno Vincenzi and Alessio Cortellini and Paolo Antonio Ascierto},
journal = {Journal of translational medicine},
year = {2026},
month = aug,
doi = {10.1186/s12967-026-08701-1},
url = {https://europepmc.org/article/MED/42968166},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Checkpoint-checkpoint combinations in cancer: from mechanistic rationale to translational impact.
AU - Alessandro Mazzocca
AU - Silvia Calagna
AU - Emanuele Claudio Mingo
AU - Silvia Cavaliere
AU - Michele Iuliani
AU - Agostina Lagodin D'Amato
AU - Luigi Scarpato
AU - Francesco Pantano
AU - Giuseppe Tonini
AU - Bruno Vincenzi
AU - Alessio Cortellini
AU - Paolo Antonio Ascierto
PY - 2026
DA - 2026/08/03
JO - Journal of translational medicine
DO - 10.1186/s12967-026-08701-1
UR - https://europepmc.org/article/MED/42968166
AB - Background Immune checkpoint inhibitors have reshaped the treatment of several cancers, producing durable responses in a subset of patients. However, most individuals either fail to respond or eventually develop resistance. Tumor immune escape results from heterogeneous and often overlapping mechanisms, including impaired antigen presentation, limited T-cell infiltration, co-expression of multiple inhibitory receptors, and suppressive tumor microenvironmental signals. These limitations have driven the development of combination strategies aimed at restoring more effective and sustained antitumor immunity.Main body Among combination approaches, dual immune checkpoint blockade represents the most established strategy. The combination of CTLA-4 and PD-1 inhibitors targets complementary phases of the immune response: early T-cell priming in lymphoid organs and effector function within the tumor microenvironment. Long-term clinical data across melanoma, lung cancer, renal cell carcinoma, mesothelioma, and hepatocellular carcinoma support the ability of this approach to induce durable survival in a meaningful proportion of patients, albeit with increased immune-related toxicity. Building on this foundation, next-generation checkpoint combinations aim to counteract adaptive resistance and T-cell exhaustion. In particular, LAG-3, TIM-3, and TIGIT are frequently co-expressed with programmed death-1 on dysfunctional T cells. Emerging checkpoints such as VISTA, B7-H3, and BTLA further expand the landscape, particularly by modulating myeloid-driven suppression and advanced T-cell dysfunction. In parallel, bispecific antibodies integrating dual checkpoint targeting within a single molecule may enhance coordinated pathway inhibition and tumor localization.Conclusion Immune checkpoint-based combinations represent an evolving strategy of immune restoration. Future advances will depend on biologically informed trial design, dynamic biomarkers, and rational optimization of dose and sequencing to maximize durable benefit while maintaining acceptable toxicity.
SN - 1479-5876
ER -