Fig. 5 |. The stromal microenvironment is functionally important for the HNSCC TME.

The head and neck squamous cell carcinoma (HNSCC) tumour microenvironment (TME) consists of a diverse stromal cell compartment — which includes cancer-associated fibroblasts (CAFs) and mesenchymal stromal cells (MSCs) — that interacts with neighbouring tumour cells and infiltrating immune cells^106,143. These interactions primarily promote tumour growth, progression and metastases but, under some conditions, can provide a supportive environment for immune cells and recruit immune cells to the HNSCC TME^132,141. Combining immune-checkpoint therapy with therapies that target the stromal compartment might improve patient outcomes in HNSCC. a, CAFs and tumour cells have a metabolic relationship mediated by hepatocyte growth factor (HGF) and basic fibroblast growth factor basic (bFGF), which increases oxidative phosphorylation (OXPHOS) in CAFs and glycolysis in tumour cells¹³⁷. Increased oxidative phosphorylation in CAFs leads to IL-6 and CXCL8 production, which suppress immune cell function^134,137. CAFs also express several immune-checkpoint ligands (ICL), including PDL1, galectin 9 (GaL9) and nectin cell adhesion molecule 2 (NECTIN2), which interact with corresponding inhibitory receptors on natural killer (NK) cells and T cells²⁸. b, MSCs can also suppress immune cell function in vitro via indoleamine-pyrrole 2,3-dioxygenase (IDO), which metabolizes tryptophan into kynurenine and is cytotoxic to T cells and NK cells^140,142,143. However, some in vitro studies suggest that MSCs can support tissue-resident memory T cells via IL-7 and IL-15 production in the presence of IFNγ and TNF¹⁴⁴. VCAM1, vascular cell adhesion protein 1.