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Review
. 2025 Apr;27(4):1426-1437.
doi: 10.1007/s12094-024-03731-x. Epub 2024 Sep 22.

Mechanisms of primary resistance to immune checkpoint inhibitors in NSCLC

Georgia Gomatou  1 , Andriani Charpidou  2 , Peifeng Li  3 , Nikolaos Syrigos  2 , Ioannis Gkiozos  2
Affiliations
Review

Mechanisms of primary resistance to immune checkpoint inhibitors in NSCLC

Georgia Gomatou et al. Clin Transl Oncol. 2025 Apr.

Abstract

Immune checkpoint inhibitors (ICIs) redefined the therapeutics of non-small cell lung cancer (NSCLC), leading to significant survival benefits and unprecedented durable responses. However, the majority of the patients develop resistance to ICIs, either primary or acquired. Establishing a definition of primary resistance to ICIs in different clinical scenarios is challenging and remains a work in progress due to the changing landscape of ICI-based regimens, mainly in the setting of early-stage NSCLC. The mechanisms of primary resistance to ICIs in patients with NSCLC include a plethora of pathways involving a cross-talk of the tumor cells, the tumor microenvironment and the host, leading to the development of an immunosuppressive phenotype. The optimal management of patients with NSCLC following primary resistance to ICIs represents a significant challenge in current thoracic oncology. Research in this field includes exploring other immunotherapeutic approaches, such as cancer vaccines, and investigating novel antibody-drug conjugates in patients with NSCLC.

Keywords: Immune checkpoint inhibitors; Immunotherapy; NSCLC; Primary resistance; Resistance.

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Conflict of interest statement

Declarations. Conflict of interest: The authors declare that they have no conflict of interest. Ethical approval: Not applicable. Informed Consent: Not applicable.

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