*Review* **Radiation-Induced Salivary Gland Dysfunction: Mechanisms, Therapeutics and Future Directions**

**Kimberly J. Jasmer 1,\*, Kristy E. Gilman 2, Kevin Muñoz Forti 1, Gary A. Weisman <sup>1</sup> and Kirsten H. Limesand <sup>2</sup>**


Received: 30 November 2020; Accepted: 17 December 2020; Published: 18 December 2020

**Abstract:** Salivary glands sustain collateral damage following radiotherapy (RT) to treat cancers of the head and neck, leading to complications, including mucositis, xerostomia and hyposalivation. Despite salivary gland-sparing techniques and modified dosing strategies, long-term hypofunction remains a significant problem. Current therapeutic interventions provide temporary symptom relief, but do not address irreversible glandular damage. In this review, we summarize the current understanding of mechanisms involved in RT-induced hyposalivation and provide a framework for future mechanistic studies. One glaring gap in published studies investigating RT-induced mechanisms of salivary gland dysfunction concerns the effect of irradiation on adjacent non-irradiated tissue via paracrine, autocrine and direct cell–cell interactions, coined the bystander effect in other models of RT-induced damage. We hypothesize that purinergic receptor signaling involving P2 nucleotide receptors may play a key role in mediating the bystander effect. We also discuss promising new therapeutic approaches to prevent salivary gland damage due to RT.

**Keywords:** radiation; hyposalivation; xerostomia; purinergic signaling; bystander effect; saliva; salivary gland; P2 receptors; radioprotection; head and neck cancer
