Advancements in TGF-β Targeting Therapies for Head and Neck Squamous Cell Carcinoma

Simple Summary TGF-beta is an important cytokine shown to drive oncogenesis in head and neck squamous cell carcinoma (HNSCC) through its diverse influences on the tumor microenvironment. While this cytokine is vital in maintaining tissue homeostasis in normal head and neck epithelia, in cancer, it paradoxically drives metastasis, angiogenesis, immune evasion, and therapy resistance. Despite promising preclinical data, the outcome of clinical trials of TGF-beta inhibitors for HNSCC has been suboptimal. Patient stratification is warranted to improve this targeted therapy.Abstract Head and neck squamous cell carcinoma (HNSCC) is the sixth leading cause of cancer worldwide according to GLOBOCAN estimates from 2022. Current therapy options for recurrent or metastatic disease are limited to conventional cytotoxic chemotherapy and immunotherapy, with few targeted therapy options readily available. Recent single-cell transcriptomic analyses identified TGF-beta signaling as an important mediator of functional interplays between cancer-associated fibroblasts and a subset of mesenchymal cancer cells. This signaling was shown to drive invasiveness, treatment resistance, and immune evasion. These data provide renewed interest in the TGF-beta pathway as an alternative therapeutic target, prompting a critical review of previous clinical data which suggest a lack of benefit from TGF-beta inhibitors. While preclinical data have demonstrated the great anti-tumorigenic potential of TGF-beta inhibitors, the underwhelming results of ongoing and completed clinical trials highlight the difficulty actualizing these benefits into clinical practice. This topical review will discuss the relevant preclinical and clinical findings for TGF-beta inhibitors in HNSCC and will explore the potential role of patient stratification in the development of this therapeutic strategy.