In Part 1, we reviewed mechanisms by which NK cells contribute to resistance against immune checkpoint blockade (ICB). In this follow-up article (Part 2), we discuss the clinical implications, potential strategies, and future directions for targeting NK cells in cancer therapy.
Clinical Implications
Multiple studies report that tumors enriched with NK cells respond poorly to ICB. This challenges the traditional paradigm of NK cells as purely beneficial, highlighting their role as modulators of therapy resistance.
Mechanisms of Suppression
- Cytokine competition (IL-2, IL-15 consumption)
- Inhibition of CD8+ T-cell differentiation and promotion of exhaustion
- Blocking T-cell infiltration via CX3CR1 axis
- Induction of suppressive mediators (e.g., TGF-β)
Therapeutic Strategies
- Depletion of suppressive NK cells: Using anti-CD38 or anti-NK1.1 antibodies to selectively eliminate tumor-associated NK subsets.
- Reprogramming NK cells: Converting dysfunctional NK cells back into antitumor effectors.
- Pathway inhibition: Targeting CX3CR1 in combination with ICB to restore T-cell infiltration.
Future Outlook
Two divergent strategies are emerging:
- Eliminating suppressive NK cells to relieve inhibition on T-cell responses.
- Enhancing cytotoxic NK subsets to directly kill tumor cells.
Rather than mutually exclusive, these approaches should be integrated, reflecting the functional diversity of NK cells in the tumor microenvironment.
My Perspective
NK cells play neither wholly “good” nor wholly “bad” roles in cancer immunity. Success in future drug development will depend on subset-specific targeting and combination regimens. Integrating ICB with NK modulation could represent the next breakthrough in immuno-oncology.
This article was edited by the Morningglorysciences team.
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