Commentary: understanding acquired resistance to immunotherapy in non-small cell lung cancer

Abstract

Programmed cell death protein ligand 1 (PD-L1) blockade has emerged as a key therapy for advanced non-small cell lung cancer (NSCLC). Unfortunately, one of the key barriers in the treatment is the acquired resistance to PD-L1, even though after the initial response to the treatment, more than 60% of the patients develop acquired resistance. In a study published in the Cancer Cell journal by Memon et al. (2024), a cohort of 1,201 patients with NSCLC was analyzed to evaluate the relapse mechanism. They identified subtypes with persistent or upregulated interferon γ (IFNγ) signaling, immune dysfunction, and antigen presentation defects. Murine models exposed to chronic IFNγ recapitulated these features, highlighting that a chronically inflamed microenvironment drives resistance. These insights underscore the need for adaptive therapies that dynamically target evolving tumor-immune interactions.

Keywords

Non-small cell lung cancer / immune checkpoint inhibitors / IFNγ signaling / acquired resistance / immunotherapy

References

[1] Memon D,Ye D.Clinical and molecular features of acquired resistance to immunotherapy in non-small cell lung cancer.Cancer Cell2024;42:209-224.e9 PMCID:PMC11249385

[2] Sharma P,Wargo JA.Primary, adaptive, and acquired resistance to cancer immunotherapy.Cell2017;168:707-23 PMCID:PMC5391692

[3] Dong S,Huang Q.Resistance to immunotherapy in non-small cell lung cancer: Unraveling causes, developing effective strategies, and exploring potential breakthroughs.Drug Resist Updat2025;81:101215

[4] Jenkins RW,Flaherty KT.Mechanisms of resistance to immune checkpoint inhibitors.Br J Cancer2018;118:9-16

[5] Le J,Deng G,Xie Y.Immune checkpoint inhibitors in cancer patients with autoimmune disease: safety and efficacy.Hum Vaccin Immunother2025;21:2458948 PMCID:PMC11792813

[6] Gettinger S,Hastings K.Impaired HLA class I antigen processing and presentation as a mechanism of acquired resistance to immune checkpoint inhibitors in lung cancer.Cancer Discov2017;7:1420-35 PMCID:5718941

[7] Alsaafeen BH,Elkord E.Resistance mechanisms to immune checkpoint inhibitors: updated insights.Mol Cancer2025;24:20

[8] Sari G.Tumor immune evasion through loss of MHC class-I antigen presentation.Curr Opin Immunol2023;83:102329 PMCID:PMC10524158

[9] Martínez-Sabadell A,Arribas J.IFNγ signaling in natural and therapy-induced antitumor responses.Clin Cancer Res2022;28:1243-9

[10] He J,Yang H.Defined tumor antigen-specific T cells potentiate personalized TCR-T cell therapy and prediction of immunotherapy response.Cell Res2022;32:530-42 PMCID:PMC9160085

[11] Dulal D,Terrero D,Tiwari AK.Tackling of immunorefractory tumors by targeting alternative immune checkpoints.Cancers2023;15:2774 PMCID:PMC10216651

[12] Zaretsky JM,Shin DS.Mutations associated with acquired resistance to PD-1 blockade in melanoma.N Engl J Med2016;375:819-29 PMCID:5007206