Immune-checkpoint inhibitors (ICIs) have transformed the treatment paradigm for advanced-stage squamous non-small-cell lung cancer (LUSC), a histological subtype associated with inferior outcomes compared with lung adenocarcinoma. However, only a subset of patients derive durable clinical benefit. In the first-line setting, multiple ICI regimens are available, including anti-PD-(L)1 antibodies as monotherapy, in combination with chemotherapy, or with an anti-CTLA4 antibody with or without chemotherapy. Several important questions persist regarding the optimal regimen for individual patients, particularly how to identify patients who might benefit from adding chemotherapy and/or anti-CTLA4 antibodies to anti-PD-(L)1 antibodies. An urgent need exists for predictive biomarkers beyond PD-L1 to better guide precision oncology approaches. Deeper knowledge of the underlying molecular biology of LUSC and its implications for response to ICIs will be important in this regard. Integration of this knowledge into multi-omics methods coupled with artificial intelligence might enable the development of more robust biomarkers. Finally, several novel therapeutic strategies, including novel ICIs, bispecific antibodies and personalized cancer vaccines, are emerging. Addressing these unresolved questions through innovative clinical trials and translational research will be crucial to further improving the outcomes of patients with LUSC. In this Review, we provide a comprehensive overview of current immunotherapeutic approaches, unresolved challenges and emerging strategies for patients with LUSC.