Immunotherapeutic strategies beyond the PD-1/PD-L1 pathway in head and neck squamous cell carcinoma – A scoping review on current developments in agents targeting TIM-3, TIGIT, LAG-3, and VISTA

• Effectiveness of PD-(L)1 targeted therapies is challenged by resistance mechanisms. • Ongoing clinical trials indicate potential benefits of combinations of inhibitory ICI inhibitors in overcoming resistance. • Further research into resistance mechanisms is necessary to improve therapy strategies and outcomes. • Moreover, research is needed to identify prior treatment impacts and find biomarkers for predicting clinical responses. Head and neck squamous cell carcinoma (HNSCC) poses a considerable challenge due to its high incidence and mortality rates. Immunotherapy targeting PD-(L)1 emerges as a promising approach for HNSCC, as it has the potential to trigger a broad and long-lasting anti-tumor response. Nevertheless, the effectiveness of immunotherapy encounters hurdles, and only a small proportion of patients benefit, with many eventually experiencing relapse. Consequently, there is a pursuit of strategies to enhance overall treatment outcomes. Understanding the mechanisms driving resistance to PD-(L)1 inhibition and devising strategies to overcome these challenges are vital for advancing more effective treatments. Furthermore, gaining insights into the mechanisms of action and safety profiles of novel combination therapies is critical for their successful adoption in clinical practice. As a result, current research is dedicated to investigating various immunotherapeutic agents beyond the PD-1/PD-L1 axis. This review offers a comprehensive overview of the existing immunotherapy strategies in HNSCC with a focus on TIM-3, TIGIT, LAG-3, and VISTA. The aim is to lay a strong foundation for the continual advancement of therapies for HNSCC.