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Unfortunately, the majority of patients with NSCLC do not respond to ICI treatment or will eventually experience disease progression. A wide variety of resistance mechanisms is hypothesized as responsible for tumor immune escape. Also, at what stage they interfere in the anticancer immune response, and the possible complex interactions or overlap between these resistance mechanisms complicate the matter further. Although progress has been made, our current understanding of the resistance mechanisms underlying the failure of ICI treatment is still limited. This is reflected in the lack of positive phase III clinical trials for second-line treatment after failure of ICI in advanced NSCLC. This might be the result of inadequate patient selection. Here, we summarize the current available data on resistance mechanisms in NSCLC and propose a classification system to categorize patients based on resistance mechanisms present. By doing so, we could guide preclinical research and improve selection of patients for clinical trials, thereby ultimately improving outcomes for patients with advanced NSCLC who have progressed on ICI.<\/jats:p>","DOI":"10.1136\/jitc-2025-013110","type":"journal-article","created":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T20:35:20Z","timestamp":1764362120000},"page":"e013110","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":8,"title":["Categorizing immunotherapy resistance mechanisms in non-small cell lung cancer: how can we perform better?"],"prefix":"10.1136","volume":"13","clinical-trial-number":[{"clinical-trial-number":"nct03546361","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0131-4672","authenticated-orcid":false,"given":"Daphne","family":"van der Geest","sequence":"first","affiliation":[{"name":"Thoracic Oncology, Netherlands Cancer Institute, Amsterdam, The 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