Krzysztof Rutkowski ¹ Michał Gola ^2,3* Janusz Godlewski ^2,4 Anna Starzynska ^5,6 Giulia Marvaso ^7,8 Federico Mastroleo ^7,8 Maria Giulia Vincini ^7,8 Alice Porazzi ⁷ Mattia Zaffaroni ⁷ Barbara Alicja Jereczek-Fossa ^7,8

• ¹ Department of Hematology, Transplantology and Internal Medicine, Medical University of Warsaw, Warsaw, Masovian, Poland
• ² Department of Human Histology and Embryology, School of Medicine, University of Warmia and Mazury in Olsztyn, Olsztyn, Warmian-Masurian, Poland
• ³ Department of Oncology and Immuno-Oncology, Clinical Hospital of the Ministry of Internal Affairs and Administration with the Warmia-Mazury Oncology Centre, Olsztyn, Warmian-Masurian, Poland
• ⁴ Surgical Oncology Clinic, Clinical Hospital of the Ministry of Internal Affairs and Administration with the Warmia-Mazury Oncology Center, Olsztyn, Warmian-Masurian Voivodeship, Poland
• ⁵ Department of Oral Surgery, Medical University of Gdańsk, Gdańsk, Pomeranian, Poland
• ⁶ Department of Otolaryngology, Phoniatrics and Audiology, Faculty of Health Sciences, Nicolaus Copernicus University in Toruń, Bydgoszcz, Pomeranian, Poland
• ⁷ Division of Radiotherapy, European Institute of Oncology (IEO), Milan, Lombardy, Italy
• ⁸ Department of Oncology and Hemato-Oncology, University of Milan, Milan, Lombardy, Italy

Worldwide, head and neck cancers (HNCs) account for approximately 900,000 cases and 500,000 deaths annually, with their incidence continuing to rise. Carcinogenesis is a complex, multidimensional molecular process leading to cancer development, and in recent years, the role of nerves in the pathogenesis of various malignancies has been increasingly recognized. Thanks to the abundant innervation of the head and neck region, peripheral nervous system has gained considerable interest for its possible role in the development and progression of HNCs. Intratumoral parasympathetic, sympathetic, and sensory nerve fibers are emerging as key players and potential targets for novel anti-cancer and pain-relieving medications in different tumors, including HNCs. This review explores nerve-cancer interactions, including perineural invasion (PNI), cancer-related axonogenesis, neurogenesis, and nerve reprogramming, with an emphasis on their molecular mechanisms, mediators and clinical implications. PNI, an adverse histopathologic feature, has been widely investigated in HNCs. However, its prognostic value remains debated due to inconsistent results when classified dichotomously (present/absent). Emerging evidence suggests that quantitative and qualitative descriptions of PNI may better reflect its clinical usefulness. The review also examines therapies targeting nerve-cancer crosstalk and highlights the influence of HPV status on tumor innervation. By synthesizing current knowledge, challenges, and future perspectives, this review offers insights into the molecular basis of nerve involvement in HNCs and the potential for novel therapeutic approaches.