Toll-like receptor 9 (TLR9) is an endosomal innate immunity receptor that plays a vital role in the first line of defense, primarily in immune cells, but in varying degrees, also in other non-immune tissues. Once TLR9 encounters its ligand, a single-stranded DNA, it activates the MyD88-dependent canonical NF-κB pathway, resulting in proinflammatory cytokine production. Besides its imperative role in defense against pathogens and resolving a tissue injury, the aberrant expression of TLR9 in multiple cancers has raised wide interest in investigating its role also in carcinogenesis.

This thesis presents new puzzle pieces for the ever-growing picture of TLR9 and its relevance to head and neck squamous cell carcinoma (HNSCC) and breast cancer (BC). The studies showed that (1) nitrogen-containing bisphosphonates (n-BPs) inhibit cell growth and viability in BC cells with suppressed TLR9-expression, (2) neither hypoxia nor TLR9 in non-immune malignant cells (i.e. tumour-originating TLR9) are essential for the HNSCC cell lines-induced alterations in uncommitted macrophage (MΦ) activity (polarisation) and functionality (cytokines), and that (3) TLR9-ligands (short cytidine-guanosine-rich oligonucleotides, CpG-ODNs) have an impact on cell migration and cell signalling on FaDu and FaDuTLR9def cells.

Although no common denominator explaining the actions of the innate immunity receptor TLR9 in BC and HNSCC was discovered, these studies demonstrate that the functions of TLR9 in cancer are often capricious and convoluted. While TLR9 is associated with the viability of BC cells upon n-BP exposure, its endogenous expression in HNSCC appears insignificant to the production of immunomodulatory molecules relevant to MΦ maturation. However, the unpublished results demonstrate that stimulation of HNSCC cells with TLR9-ligands modulates their cell physiology as well as signalling. Since the outcome of TLR9-mediated alterations can be proor anti-tumorigenic depending on the context, its utility as a biomarker needs more research. These findings warrant clinician awareness when assessing and interpreting outcomes after novel cancer treatments, such as TLR9-binding oligonucleotides as cancer vaccine adjuvants.