Immune Cell Engagers and “Masking Immunotherapy” for Solid Tumors: Focus on Head and Neck Cancers
- 1Head and Neck Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy
- 2Integrated Biology of Rare Tumors, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy
- 3Department of Oncology and Hemato-Oncology, University of Milan, 20122 Milan, Italy
Abstract
Head and neck squamous cell carcinomas (HNSCCs) are challenging pathologies to treat with immune checkpoint inhibitors (ICIs), as only a minority of patients achieve durable clinical benefit. The highly immunosuppressive tumor microenvironment (TME), the frequent loss of antigen presentation, the marked spatial heterogeneity, and the anatomical proximity of tumors to critical structures limit the efficacy and safety of current immunotherapeutic approaches. Immune cell engagers (ICEs) have emerged as promising strategies to redirect endogenous immune cells toward tumor targets. While conventional surface-antigen-directed engagers can bypass major histocompatibility complex (MHC)-restricted antigen presentation, peptide–HLA-directed constructs remain dependent on antigen processing, peptide presentation, and the appropriate HLA allele. More recently, tumor-restricted activation technologies, collectively referred to as “masking immunotherapy”, have been developed to preferentially restore target and/or immune-cell engagement under TME-associated conditions, such as increased protease activity. These approaches have demonstrated enhanced tumor-preferential activity and/or improved tolerability in preclinical models; however, the extent to which these properties translate into clinically meaningful tumor selectivity and an improved therapeutic index remains under investigation. In this review, based on the authors’ comprehensive literature knowledge and targeted searches, we critically examine the biological rationale, the engineering principles, the current preclinical evidence, and the early clinical development of ICEs with particular emphasis on their potential application in HNSCC. While early clinical studies have demonstrated acceptable safety profiles, clinical activity has generally been poor. We discuss the major barriers that limit clinical translation and we highlight emerging strategies aimed at overcoming these limitations. We believe that successful clinical development of ICEs in HNSCC will likely depend not only on the identification of optimal target antigens, but also on spatially controlled immune activation, integration with TME-modulating approaches, and incorporation of dynamic biomarkers into future clinical trial design.
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BibTeX
@article{nardo2026immune,
title = {{Immune Cell Engagers and “Masking Immunotherapy” for Solid Tumors: Focus on Head and Neck Cancers}},
author = {Giuseppe Nardo and Deborah Lenoci and Marta Lucchetta and Lisa Licitra and Loris De Cecco and Stefano Cavalieri},
journal = {Cancers},
year = {2026},
month = oct,
doi = {10.3390/cancers18203401},
url = {https://www.mdpi.com/2072-6694/18/20/3401},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Immune Cell Engagers and “Masking Immunotherapy” for Solid Tumors: Focus on Head and Neck Cancers
AU - Giuseppe Nardo
AU - Deborah Lenoci
AU - Marta Lucchetta
AU - Lisa Licitra
AU - Loris De Cecco
AU - Stefano Cavalieri
PY - 2026
DA - 2026/10/01
JO - Cancers
DO - 10.3390/cancers18203401
UR - https://www.mdpi.com/2072-6694/18/20/3401
AB - Head and neck squamous cell carcinomas (HNSCCs) are challenging pathologies to treat with immune checkpoint inhibitors (ICIs), as only a minority of patients achieve durable clinical benefit. The highly immunosuppressive tumor microenvironment (TME), the frequent loss of antigen presentation, the marked spatial heterogeneity, and the anatomical proximity of tumors to critical structures limit the efficacy and safety of current immunotherapeutic approaches. Immune cell engagers (ICEs) have emerged as promising strategies to redirect endogenous immune cells toward tumor targets. While conventional surface-antigen-directed engagers can bypass major histocompatibility complex (MHC)-restricted antigen presentation, peptide–HLA-directed constructs remain dependent on antigen processing, peptide presentation, and the appropriate HLA allele. More recently, tumor-restricted activation technologies, collectively referred to as “masking immunotherapy”, have been developed to preferentially restore target and/or immune-cell engagement under TME-associated conditions, such as increased protease activity. These approaches have demonstrated enhanced tumor-preferential activity and/or improved tolerability in preclinical models; however, the extent to which these properties translate into clinically meaningful tumor selectivity and an improved therapeutic index remains under investigation. In this review, based on the authors’ comprehensive literature knowledge and targeted searches, we critically examine the biological rationale, the engineering principles, the current preclinical evidence, and the early clinical development of ICEs with particular emphasis on their potential application in HNSCC. While early clinical studies have demonstrated acceptable safety profiles, clinical activity has generally been poor. We discuss the major barriers that limit clinical translation and we highlight emerging strategies aimed at overcoming these limitations. We believe that successful clinical development of ICEs in HNSCC will likely depend not only on the identification of optimal target antigens, but also on spatially controlled immune activation, integration with TME-modulating approaches, and incorporation of dynamic biomarkers into future clinical trial design.
SN - 2072-6694
ER -