NK cell - Dress Code for Killing

...molecular choreography when a natural killer (NK) cell “gets dressed to kill” a tumor cell.

Molecular Steps of NK Cell–Mediated Tumor Cell Killing

1. Tumor Cell Recognition

NK cells don’t rely on a single receptor like TCR, but integrate signals from a complex set of activating and inhibitory receptors:

• Inhibitory receptors (checkpoints for tolerance):

  • KIRs (Killer-cell immunoglobulin-like receptors) bind MHC-I (HLA-A/B/C).

  • NKG2A/CD94 binds HLA-E.→ If normal MHC-I is present, these receptors deliver ITIM signals → recruit SHP-1/2 phosphatases → block activation.

• Activating receptors (danger sensors):

  • NKG2D recognizes MICA/MICB, ULBPs (stress-induced ligands).

  • DNAM-1 (CD226) recognizes CD112 (Nectin-2) and CD155 (PVR).

  • Natural cytotoxicity receptors (NCRs: NKp30, NKp44, NKp46) bind viral/tumor ligands.

  • CD16 (FcγRIIIa) mediates ADCC by binding IgG-coated tumor cells.

Balance of signals decides: If inhibitory input is low (e.g., tumor cells often downregulate MHC-I) and activating input is high, the NK cell commits to kill.

2. Immunological Synapse Formation

Once activated, NK cells polarize toward the tumor cell:

• Adhesion molecules:

  • LFA-1 (CD11a/CD18) on NK binds ICAM-1 on tumor.

  • Forms a stable immune synapse.

• Inside NK cell:

  • Actin cytoskeleton reorganizes.

  • Microtubule organizing center (MTOC) reorients toward the synapse.

  • Lytic granules (containing perforin & granzymes) traffic to the contact site.

3. Cytotoxic Arsenal Release

NK cells have two main molecular killing strategies:

(A) Granule Exocytosis Pathway

• Perforin inserts into tumor cell membrane → polymerizes → forms pores.

• Granzymes (mainly Granzyme B, A, M) enter cytosol via perforin pores or endocytosis.

  • Granzyme B cleaves caspases (e.g., caspase-3, caspase-7) and BID → apoptosis.

  • Granzyme A triggers caspase-independent apoptosis via DNA damage (nuclease activation).

• Serglycin stabilizes perforin/granzymes in lytic granules.

(B) Death Receptor Pathway

• NK cells express FasL (CD95L) and TRAIL.

• Bind Fas (CD95) and TRAIL-R1/R2 on tumor → recruit FADD → activate caspase-8 → apoptosis.

4. Cytokine and Chemokine Assault

NK cells also modulate the tumor microenvironment:

• IFN-γ: Activates macrophages, boosts antigen presentation, shapes adaptive immunity.

• TNF-α: Directly cytotoxic, pro-apoptotic via TNFR1.

• GM-CSF, CCL3, CCL4, CCL5: Recruit dendritic cells, T cells, more NK cells.

5. Molecular Checkpoints & Tumor Evasion

Tumors evolve to resist NK attack:

• Upregulating MHC-I → strengthens inhibitory KIR signals.

• Shedding NKG2D ligands (MICA/B) → soluble decoys bind NKG2D and block activation.

• Expressing PD-L1 → inhibits NK and T cells via PD-1.

• Immunosuppressive cytokines (TGF-β, IL-10) → reduce NK receptor expression and cytotoxicity.

6. NK Cell “Dress Code for Killing”

When NK cells activate fully, their molecular “armor” includes:

• Upregulated perforin + granzyme release machinery.

• Polarized MTOC + lytic granules aligned to the synapse.

• Enhanced cytotoxic receptors (NKG2D, NCRs, CD16).

• Secretion of IFN-γ + TNF-α to orchestrate the immune assault.

✅ In summary:NK cells kill tumor cells by sensing missing-self (low MHC-I) and induced-self ligands (stress markers), forming a tight synapse, delivering perforin/granzymes or death ligands, and reinforcing with cytokine-mediated immune pressure. Tumor cells, in turn, deploy molecular tricks to escape this immune surveillance.