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Addressing clinical needs in NSCLC immunotherapy: Mechanisms of resistance and promising combination strategies

Kai Kang1, Shanghai Liu1, Zhuoran Yao1

  • 1Division of Thoracic Tumor Multimodality Treatment and Department of Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China; Laboratory of Clinical Cell Therapy, West China Hospital, Sichuan University, Chengdu, China; Tianfu Jincheng Laboratory, Chengdu, China.

Cell Reports. Medicine
|August 28, 2025
PubMed

Insights

Programmed cell death protein 1 (PD-1) and PD-1 ligand (PD-L1) immunotherapies are vital for non-small cell lung cancer. Understanding resistance mechanisms is key to developing effective combination strategies for improved patient outcomes.

Area of Science:

  • Oncology
  • Immunology
  • Clinical Trials

Background:

  • Programmed cell death protein 1 (PD-1) and PD-1 ligand (PD-L1) monoclonal antibody immunotherapy is a primary treatment for non-small cell lung cancer (NSCLC) lacking driver gene alterations.
  • Therapeutic resistance, both primary and acquired, presents a significant clinical obstacle, impacting treatment efficacy and patient prognosis.

Purpose of the Study:

  • To review the mechanisms of resistance to PD-(L)1 immunotherapy in NSCLC.
  • To explore potential combination strategies to overcome immunotherapy resistance.
  • To highlight considerations for future clinical trial design in NSCLC immunotherapy.

Main Methods:

  • Analysis of delayed progression-free survival curve separation in randomized clinical trials.
  • Review of biological mechanisms underlying tumor-immune interactions and resistance.
  • Synthesis of current literature on immunotherapy resistance and combination therapies.

Main Results:

  • Delayed separation of progression-free survival curves indicates evolving resistance and dynamic anti-tumor immunity.
  • Understanding complex tumor-immune interactions is crucial for designing effective combination therapies.
  • Various mechanisms contribute to primary and acquired resistance to PD-(L)1 inhibitors.

Conclusions:

  • Effective combination strategies require a deep understanding of resistance mechanisms.
  • Future clinical trials should focus on therapy sequencing, biomarker-guided selection, and toxicity management.
  • Optimizing combination immunotherapy is essential for improving outcomes in NSCLC patients resistant to PD-(L)1 treatment.
Keywords:
combination treatmentimmunotherapy resistancenon-small cell lung cancer

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