ABSTRACT The goal of this study is to understand psychosocial sequelae and their biological and social determinants among patients with advanced head and neck cancer (HNC) receiving immunotherapy. Immunotherapy has recently been approved by the FDA for advanced HNC. Patients with advanced cancer often experience substantial clinical prognostic uncertainty, leading to increased psychosocial burden, which, in turn, contributes to worse survival, including in HNC. However, evidence on immunotherapy-related psychosocial burdens is not well-documented, particularly for HNC. Patients with HNC suffer a high psychosocial burden before immunotherapy, likely due to common and long-lasting disease- and treatment-induced side effects (e.g., dry mouth, difficulty opening mouth, and mucositis) that uniquely and significantly impact HNC patients’ critical daily functions (e.g., eating and speaking). These psychosocial burdens are speculated to be even higher among those receiving immunotherapy due to advanced cancer stage and uncertainty from immunotherapy length and side effects. Given the scarce evidence, there is a pressing need to investigate psychosocial sequelae (e.g., fatigue, depression) among patients receiving immunotherapy so that specialized care can be targeted to improve QOL and long-term survival. Additionally, identifying biological and social determinants of psychosocial sequelae will highlight risk factors and provide instrumental guidance on interventional strategies. We and others have found that greater inflammation is associated with worse symptomatic side effects, including psychosocial symptoms, and poorer QOL and survival in cancer patients. Nevertheless, whether immunotherapy-associated inflammation is part of the biological determinants of psychosocial sequelae is unknown. Furthermore, an emerging appreciation of the gut-brain connection has suggested the involvement of the gut microbiome in psychosocial sequelae. Our preliminary data show that inflammation-related taxa are linked with high psychosocial sequelae, suggesting that restoration of depleted bacteria or their metabolites has the potential to reverse the dysbiosis-associated phenotypes. Still, larger studies are warranted to validate the findings before the development of individual, targeted interventions. Social determinants also impact a wide range of health-related conditions and contribute substantially to health disparities. However, whether and how environmental/community social determinants influence patients’ psychosocial sequelae among those receiving immunotherapy is unclear. Therefore, we propose investigating biological and social determinants of psychosocial outcomes for HNC patients receiving immunotherapy. The findings from the study will be instrumental in developing not only individual, personalized, targeted interventions (informed by biological determinants) but also public health and community-level interventions (informed by social determinants), with t...