The treatment landscape of non-small-cell lung cancer (NSCLC) has evolved considerably with the integration of immune-checkpoint inhibitors (ICIs) into first-line regimens. However, the majority of patients will ultimately have primary resistance or develop secondary resistance, driven by a complex interplay of intrinsic tumour biology and adaptive changes within the tumour microenvironment (TME), which can be further amplified by host-related factors such as dysbiosis and organ-specific conditions. Despite these heterogeneous origins, most mechanisms of resistance to ICIs lead to an immunosuppressive TME as the final common pathway. Consequently, current strategies designed to overcome resistance aim to restore antitumour immunity via antibody-based therapies (including bispecific antibodies, T cell engagers and antibody-drug conjugates), targeted therapies, adoptive cell therapies, therapeutic vaccines or intratumoural immunotherapies. Although substantial progress has been made in identifying potential biomarkers associated with immune resistance, the clinical relevance of many of these observations remains limited. Biomarker-driven studies using adaptive, hypothesis-generating designs might offer a promising path forward by navigating the complexity of resistance and enabling the timely evaluation of novel therapeutic concepts. In this Review, we summarize the latest advances in addressing resistance to ICIs in patients with advanced-stage NSCLC and provide insights into emerging clinical strategies and future research directions.