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Categorizing immunotherapy resistance mechanisms in non-small cell lung cancer: how can we perform better?

Daphne van der Geest1, Alex van Vliet2, Daniel S Peeper2

  • 1Thoracic Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands d.vd.geest@nki.nl.

Journal for Immunotherapy of Cancer
|November 28, 2025
PubMed

Insights

Immune checkpoint inhibitors (ICI) show promise for advanced non-small cell lung cancer (NSCLC). However, many patients don't respond due to resistance mechanisms, necessitating better patient selection for improved outcomes.

Area of Science:

  • Oncology
  • Immunotherapy
  • Cancer Research

Background:

  • Immune checkpoint inhibitors (ICI) have transformed advanced non-small cell lung cancer (NSCLC) treatment.
  • However, a significant number of NSCLC patients exhibit primary or acquired resistance to ICI therapy.
  • Limited understanding of resistance mechanisms hinders the development of effective second-line treatments.

Purpose of the Study:

  • To summarize current knowledge on NSCLC resistance mechanisms to ICI.
  • To propose a classification system for categorizing patients based on resistance profiles.
  • To guide preclinical research and enhance patient selection for clinical trials.

Main Methods:

  • Review of existing literature on ICI resistance in NSCLC.
  • Analysis of proposed resistance mechanisms and their interactions.
  • Development of a novel classification framework for resistance mechanisms.

Main Results:

  • Multiple, complex resistance mechanisms contribute to ICI failure in NSCLC.
  • Current understanding of these mechanisms and their clinical implications remains incomplete.
  • A systematic classification of resistance mechanisms is lacking.

Conclusions:

  • A deeper understanding of resistance mechanisms is crucial for overcoming ICI failure in NSCLC.
  • A proposed classification system can aid in stratifying patients for targeted therapies.
  • Improved patient selection based on resistance mechanisms may enhance clinical trial success and patient outcomes.
Keywords:
Immune Checkpoint InhibitorImmunotherapyLung Cancer

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