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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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Overcoming Primary and Acquired Resistance to Immunotherapy in Non-Small Cell Lung Cancer: Mechanisms, Challenges,

Cassio Murilo Hidalgo-Filho1,2,3, Valentina Santo1, Eleonora Gariazzo1

  • 1Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
|May 22, 2026
PubMed

Insights

Acquired resistance to immune checkpoint inhibitors (ICIs) is a challenge in non-small cell lung cancer (NSCLC). This review explores mechanisms of resistance and novel strategies to restore antitumor immunity for better patient outcomes.

Area of Science:

  • Oncology
  • Immunology
  • Cancer Research

Background:

  • Acquired resistance (AR) to immune checkpoint inhibitors (ICIs) limits durable clinical benefit in non-small cell lung cancer (NSCLC).
  • AR involves tumor evolution, immune escape, and metabolic reprogramming.
  • Mechanisms include impaired antigen presentation, T-cell exhaustion, and tumor microenvironment (TME) remodeling.

Purpose of the Study:

  • To review current understanding of ICI resistance in NSCLC.
  • To highlight emerging therapeutic strategies to overcome AR.
  • To discuss approaches for achieving durable, personalized immunotherapy outcomes.

Main Methods:

  • Literature review of current understanding of ICI resistance mechanisms.
  • Summary of novel therapeutic strategies under investigation.
  • Discussion of biomarker-driven patient selection and combination therapies.

Main Results:

  • Key resistance mechanisms identified: antigen presentation defects, T-cell exhaustion, TME changes.
  • Investigational strategies include next-generation ICIs, epigenetic and metabolic modulators.
  • Cellular immunotherapies, ADCs, and vaccines offer complementary approaches.

Conclusions:

  • Overcoming AR in NSCLC requires understanding complex resistance mechanisms.
  • Novel therapeutic combinations targeting TIGIT, LAG-3, epigenetic, and metabolic pathways show promise.
  • Biomarker-driven selection and rational combinations are crucial for durable immunotherapy responses.

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