Innovative organ-on-a-chip platforms for exploring tumorigenesis and therapy in head and neck cancer

Abstract

Background: Head and neck cancer (HNC) presents significant research challenges due to the complexity of its tumor microenvironment (TME) and the heterogeneity across different cancer subtypes. Recent advancements in three-dimensional (3D) culture models and organ-on-a-chip (OOC) technology offer new avenues for mimicking the TME and enhancing the study of tumor biology, drug responses, and personalized treatment strategies. This study aims to summarize the current state of these models in HNC research and their potential in bridging the gap between preclinical models and clinical applications.

Methods: This review synthesizes findings from recent literature on the use of 3D models such as tumor spheroids, organoids, and co-culture systems in HNC research. A focus is placed on their applications in different cancer types, including laryngeal, oral, and nasopharyngeal cancers. Additionally, the integration of OOC technology in studying cancer metastasis, immunotherapy, and radiotherapy is discussed. Relevant studies on the role of AI and robotics in improving model efficiency and scalability are also examined.

Results: The review identifies key developments in 3D model systems and OOC technologies, highlighting their ability to replicate patient-specific tumor behaviors and predict therapeutic responses. While these models have advanced the understanding of HNC pathophysiology, challenges remain in terms of technical limitations, validation, and physiological relevance. The integration of AI and robotics has shown promise in enhancing the scalability and data analysis capabilities of these models.

Conclusions: Advancements in 3D and OOC technologies are essential for overcoming the current limitations in HNC research. These models offer valuable insights into tumor biology and therapeutic efficacy, and their integration with artificial intelligence (AI) can further accelerate the development of personalized treatment strategies. However, further validation and refinement are needed before these models can be widely translated into clinical practice, offering a more effective and individualized approach to treating HNC.

Keywords: Head and neck Cancer (HNC); Organ-on-a-Chip (OOC); Personalized medicine; Three-Dimensional models (3D); Tumor microenvironment (TME).

Fig. 1

Head and Neck Cancer and Its Complex Microenvironment A. The most frequent sites of head and neck tumors include: (1) oral cavity, (2) pharynx, (3) larynx, (4) nasal cavity, and (5) thyroid; B. The HNC tumor microenvironment (TME) consists of cancer cells, stromal cells (e.g., cancer-associated fibroblasts), immune cells (e.g., B cells, T cells, Natural Killer cells), and extracellular matrix (ECM) components (e.g., collagen, fibronectin), which collectively support tumor progression and therapy resistance. Abbreviations: CAF, cancer-associated fibroblast; VEGF, vascular endothelial growth factor; TAM, tumor-associated macrophage; TAN, tumor-associated neutrophil

Fig. 2

Different organ-on-chip designs are tailored for various research purposes (A) Single-chamber chip design. Reproduced with permission [71].Copyright 2023, Proceedings of the National Academy of Sciences of the United States of America; (B) High-throughput multi-array chip. Reproduced with permission [72]. Copyright 2021, Toxicology; (C) Parallel chamber chip. Reproduced with permission [73].Copyright 2021, Nature biomedical engineering; (D) Dual-organ and multi-organ interconnected chip platforms. Reproduced with permission [74, 75]. Copyright 2018, Scientific reports; Copyright 2020, Nature biomedical engineering

Fig. 3

Application of Organ-on-a-chip in tumor metastasis and drug testing. (A) Co-culture of renal carcinoma Caki-1 cells and CAFs in a chip-model biomimetic liver microenvironment. Reproduced with permission [86]. Copyright 2021, Theranostics; (B) Multi-organ metastasis-on-a-chip model. Reproduced with permission [87]. Copyright 2016, ACS Applied Materials & Interfaces; (C) Lung cancer organoid drug testing model with CGG for screening patient-derived organoids and identifying optimal drug concentrations. Reproduced with permission [89]. Copyright 2013, Biomaterials; (D) a high-throughput chip model to test anti-PD-1 effects on breast cancer spheroids and T cells, using microcolumn arrays to monitor tumor-immune interactions. Reproduced with permission [91]. Copyright 2021, Small

Fig. 4

Representative HNC 3D model applications (A) 3D TRACERs co-culture model of cancer-associated fibroblasts and HNSCC cells. Reproduced with permission [90]. Copyright 2021, Biomaterials; (B) 3D oral cancer model simulating tumor progression and testing nanoparticle-based drug delivery systems. Reproduced with permission [93]. Copyright 2023, In Vivo; (C) Air-liquid interface 3D culture model of nasopharyngeal carcinoma to study disease progression and EBV infection. Reproduced with permission [95]. Copyright 2018, mSphere

Fig. 5

Representative organ-on-a-chip studies related to head and neck cancer (A) Respiratory chip derived from nasal cavity, consisting of three layers: epithelial, fibroblast, and endothelial layers. Reproduced with permission [104]; (B) Microfluidic chip design for tongue cancer. Immune cells are loaded in channel A, tongue cancer cells in channel B, and channel C is used for hydration. Reproduced with permission [110]; (C) Oral cancer organ-on-a-chip simulating the tumor microenvironment, schematic and in vitro characterization. Reproduced with permission [112]

Fig. 6

Construction strategy of HNC Tumor-on-a-chip