AccScience Publishing / TD / Online First / DOI: 10.36922/TD025110020
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REVIEW ARTICLE

Mechanisms of resistance to immunotherapy in lung cancer: A review

Helmut H. Popper1*
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1 Diagnostic and Research Institute of Pathology, Medical University of Graz, Graz, Styria, Austria
Tumor Discovery, 025110020 https://doi.org/10.36922/TD025110020
Received: 11 March 2025 | Revised: 13 May 2025 | Accepted: 30 May 2025 | Published online: 31 December 2025
© 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

Pulmonary carcinomas have developed several mechanisms to evade immune cell attack. Among these mechanisms, the programmed death 1 (PD-1), programmed death ligand 1 and 2 (PD-L1/2), and the cytotoxic T-lymphocyte-associated protein 4 system have garnered particular interest. Tumor cells and lymphocytes express ligands for PD-1, which induce apoptosis or exhaustion of CD8 T cells. This further impacts the microenvironment (MEV) composed of cytokines, leading to immune tolerance. Therapies targeting PD-L1 expression have shown significant success in restoring the function of T-lymphocytes against tumor cells. Antibodies against the PD-1 receptor have been developed and tested in clinical trials with positive outcomes. Immunohistochemistry tests for PD-1 and PD-L1 expression are used to select patients likely to respond to this therapy. A strong PD-L1 staining in at least 1% of tumor cells and/or lymphocytes (or 50% in one trial) was considered a positive result and was associated with patient prognosis. This criterion was used to determine eligibility for anti-PD-L1 therapy. However, PD-L1 expression thresholds vary across clinical trials and therapeutic agents, with some drugs requiring PD-L1 positivity in ≥50% of tumor cells. Based on data from previous clinical trials, most patients were diagnosed using this simple staining method. However, false-positive and false-negative results have been reported in some patients. Resistance and immune escape mechanisms of pulmonary carcinoma have been extensively investigated. Some of these mechanisms involve the metabolic reprogramming of tumor cells within the tumor MEV. Several immune checkpoint molecules have been identified and further tested. In addition, the composition of the tumor stroma, including various types of lymphocytes and dendritic cells, has gained considerable attention.

Keywords
Programmed death 1-programmed death ligand 1
Cytotoxic T-lymphocyte-associated protein 4
Lymphocyte activation gene 3
T-cell immunoglobulin and mucin domain-3
Glucocorticoid-induced tumor necrosis factor receptor family-related protein
Cytotoxic T cell
Dendritic cell
Metabolites
Funding
None.
Conflict of interest
Helmut H. Popper is the Editor-in-Chief of this journal and Guest Editor of this special issue, but was not in any way involved in the editorial and peer-review process conducted for this paper, directly or indirectly. The author declared that he has no known competing financial interests or personal relationships that could have influenced the work reported in this paper.
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Tumor Discovery, Electronic ISSN: 2810-9775 Print ISSN: 3060-8597, Published by AccScience Publishing
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