Immune Cell Engagers and “Masking Immunotherapy” for Solid Tumors: Focus on Head and Neck Cancers

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.