Immunotherapy has revolutionized cancer treatment. Despite its success across various malignancies, a significant proportion of patients either fail to respond (primary resistance) or relapse after an initial response (acquired resistance). This review explores the different mechanisms underlying resistance to immunotherapy, including tumor-intrinsic factors such as loss of antigen presentation, genetic, and epigenetic mutations. It also examines tumor-extrinsic contributors, such as immunosuppressive cells in the tumor microenvironment, checkpoint molecule upregulation, and microbiome influences. A comprehensive understanding of resistance mechanisms is essential for improving patient selection, developing combination therapies, and ultimately enhancing the efficacy and durability of immunotherapeutic interventions.

Non-small cell lung cancer (NSCLC) accounts for up to 85% of lung cancer cases, with activating EGFR mutations present in 10–15% of Western and up to 35% of Asian patients. EGFR tyrosine kinase inhibitors (TKIs) have transformed management, with first-line osimertinib demonstrating a median progression-free survival (PFS) of 18.9 months and overall survival (OS) of 38.6 months in the FLAURA trial. However, resistance inevitably develops, most commonly via T790M mutations (~50% of cases after first- and second-generation TKIs), and after osimertinib, through diverse mechanisms including C797S mutations, MET/HER2 amplification, and histologic transformation. Emerging strategies to overcome resistance include next-generation TKIs, combination targeted therapies, downstream pathway inhibitors, immunotherapy approaches, and antibody–drug conjugates. Understanding these mechanisms is critical for optimizing patient outcomes and guiding personalized therapeutic approaches. This review discusses current strategies to delay or overcome resistance and highlights emerging therapeutic avenues with the potential to reshape the management of EGFR-mutant NSCLC.