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Updated: May 27, 2025

Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
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Primary and Acquired Resistance to Immunotherapy with Checkpoint Inhibitors in NSCLC: From Bedside to Bench and Back

Annapaola Mariniello1, Maxime Borgeaud1, Marc Weiner1

  • 1Oncology Department, University Hospital Geneva, rue Perret-Gentil 4, 1205, Geneva, Switzerland.

Biodrugs : Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy
|February 15, 2025
PubMed

Insights

Most patients with non-small cell lung cancer (NSCLC) do not respond to immunotherapy or develop resistance. This review explores resistance mechanisms and strategies to improve immunotherapy effectiveness in NSCLC.

Area of Science:

  • Oncology
  • Immunology
  • Translational Medicine

Background:

  • Immunotherapy, particularly checkpoint inhibitors targeting PD-1, is a primary treatment for non-small cell lung cancer (NSCLC) lacking oncogene addiction.
  • A significant majority of patients (70-85%) show primary resistance or develop acquired resistance to these therapies, even with combination treatments.

Purpose of the Study:

  • To review definitions and explore proposed mechanisms of primary and acquired resistance to cancer immunotherapy in NSCLC.
  • To discuss adaptive changes in tumors and immune cells after checkpoint inhibitor exposure.
  • To provide an overview of current and emerging therapeutic strategies to overcome resistance.

Main Methods:

  • Literature review of definitions and proposed mechanisms of immunotherapy resistance.
  • Analysis of translational data on adaptive changes in tumor cells and immune infiltrates.
  • Synthesis of current and emerging therapeutic strategies.

Main Results:

  • Resistance to immunotherapy in NSCLC is multifaceted, involving tumor microenvironment, systemic factors, and intrinsic tumor characteristics.
  • Adaptive changes in tumor cells and immune cells occur post-treatment, contributing to resistance.
  • Numerous therapeutic strategies are under investigation to enhance immunotherapy efficacy.

Conclusions:

  • Understanding resistance mechanisms is crucial for improving patient outcomes in NSCLC immunotherapy.
  • Targeting resistance pathways and adaptive changes holds promise for overcoming non-response and acquired resistance.
  • Further research into predictive biomarkers and novel therapeutic combinations is essential.

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