Chapter 6 │ Page 207 are known to brake their function. In addition, assessment of MICA/B molecules, critical ligands for the NKG2D receptor, showed an upregulation 24 hours posttreatment. NKG2D is a potent activating receptor on NK cells that recognizes multiple NKG2D ligands, including MICA/B, markers that are typically retained intracellularly in healthy cells, but become overexpressed in stressed or transformed cells [46, 47]. Considering the crucial input of activating and inhibiting signals to determine NK cell function [48-53], the observed shift in ligand expression suggests that NTP may directly alter the tumor cell profile to be more recognizable and vulnerable to NK cells. Only a few reports are available on this topic, including the study of Clemen et al., which demonstrated increased NK cell activity towards NTP-treated melanoma cells that was linked to an improved immunogenicity of the cancer cells [54]. Hence, our work builds on this limited body of literature, and provides an important contribution to current knowledge. Specifically, we show that NTP impacts a broad range of both inhibitory and activating ligands involved in NK cell recognition and activation, and this ligand-focused analysis can serve as a valuable resource for future in-depth investigations into specific ligand-receptor interactions and their role in NK cell function, to ultimately establish NTP as an innate immune modulator. 2. FUTURE PERSPECTIVES Considering the promising immunogenic e ects of NTP in combination with standard-of-care CDDP in HNSCC, its therapeutic potential could also extend to other malignancies. ICIs and platinum-based chemotherapy are widely used across multiple cancer types, so NTP could also serve as a valuable adjuvant strategy for these tumors to enhance their immunogenicity. Melanoma represents the most successful application of ICI therapy to date, and also for other solid tumors like metastatic non-small cell lung cancer (NSCLC) and triple-negative breast cancer (TNBC), ICI, either as monotherapy or in combination with chemotherapy, is
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