Unleashing NK cells for cancer immunotherapy in lung cancer: biologic challenges and clinical advances
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Updated: Sep 10, 2025
Advances in Human Induced Pluripotent Stem Cell-Derived Chimeric Antigen Receptor-Expressing Natural Killer Cells
Published on: February 14, 2025
Quinlan McLaughlin1, Dorothy K Sojka2, Kathleen Kennedy3
1Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA.
Abstract:
Natural killer (NK) cells are a crucial part of the innate immune system and serve as an important effector for killing tumor cells through direct cytolytic activity or immunomodulatory signaling to T cells and antigen presenting cells. NK cells are correlated with increased tumor control and better overall patient survival across various types of cancers including non-small cell lung cancer (NSCLC). Despite their promising potential for anti-tumor killing, NK cell function is often diminished within the tumor microenvironment. There are many factors that lead to decreased tumor-infiltrating NK cell killing, including immunoinhibitory factors from tumor cells and resident tissues, acquired immune tolerance, NK cell exhaustion, and the hypoxic state of the tumor microenvironment. Unleashing NK cell activity therefore has high potential to create a new class of immunotherapy that could combat both primary and acquired resistance to current checkpoint inhibitors. In this review we discuss mechanistic details of NK cell tumor killing, NK cell immunosuppression, and gaps in knowledge regarding highly complex microenvironment-specific effects on NK cell function. We also discuss the promise and limitations of emerging NK-cell based therapeutic strategies.
Insights
Natural killer (NK) cells fight tumors but are suppressed in the tumor microenvironment. Understanding NK cell activity and suppression is key to developing new immunotherapies for cancer patients.
Area of Science:
- Immunology
- Oncology
Background:
- Natural killer (NK) cells are vital for innate immunity and tumor surveillance.
- NK cell activity correlates with improved cancer control and survival in patients with non-small cell lung cancer (NSCLC).
Purpose of the Study:
- To review the mechanisms of NK cell-mediated tumor killing.
- To explore factors suppressing NK cell function within the tumor microenvironment.
- To discuss the potential and challenges of NK cell-based cancer immunotherapies.
Main Methods:
- Literature review of NK cell function in cancer.
- Analysis of mechanisms underlying NK cell immunosuppression in tumors.
- Evaluation of current and emerging NK cell therapeutic strategies.
Main Results:
- NK cell function is often impaired in the tumor microenvironment due to factors like immunosuppressive signals, immune tolerance, exhaustion, and hypoxia.
- Overcoming NK cell suppression offers a promising avenue for novel immunotherapies.
- Existing NK cell-based strategies face limitations that require further research.
Conclusions:
- NK cells are potent anti-tumor effectors, but their efficacy is compromised within the tumor microenvironment.
- Targeting NK cell suppression is a critical strategy for enhancing cancer immunotherapy.
- Further research is needed to optimize NK cell-based therapies for clinical application.
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