Chapter 1 │ Page 19 multiple cancer types (e.g. glioblastoma[87], bladder[67], and pancreatic cancer[88]), it is not surprising that the most significant advancements have been made in tumors that are anatomically accessible, such as melanoma and HNSCC, allowing for direct NTP application. However, beyond these practical considerations, the focus on HNSCC is also driven by the pressing clinical need of advanced patients, who often face limited treatment options and poor prognosis, especially in the recurrent and refractory setting [89]. The unique anatomy of the head and neck region encompasses many delicate structures essential for breathing, speaking, and swallowing, thereby making a highly-localized therapy like NTP very appealing. The direct physical penetration of reactive NTP components is believed to be limited to the micrometer range, supporting the concept of a highly localized and tissue-sparing treatment [90]. Interestingly, biological e ects have been observed far beyond this depth, including shrinkage of much larger subcutaneous tumors after NTP exposure [64, 88]. This suggests that NTP’s therapeutic impact may involve both direct and indirect mechanisms, a research topic that remains crucial to explore for a full understanding of its e icacy and safety. While initial clinical introduction has focused on the palliative setting for patients without further treatment options, I envision a broader role for NTP as a potent therapy addition for advanced HNSCC. Indeed, standard treatments like surgery and radiotherapy are e ective in early-stage, localized disease. However, in more advanced cases, particularly when systemic approaches such as a chemoradiation, or immunotherapy with or without chemotherapy are the first-line approach and complete resection is not immediately an option, NTP could contribute to improved local tumor control, total tumor load reduction, or increased sensitivity to other treatments in both an adjuvant or neo-adjuvant setting. Nevertheless, fully realizing this potential will also require a deeper understanding of NTP’s immunomodulatory e ects, as these could play a crucial role in its integration into modern immune-based treatment strategies.
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