execution phase of tumor cell killing

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..let´s dive into the final execution phase of tumor cell killing on the molecular level. Think of this as the crescendo of the immune orchestra, where every arm converges to ensure tumor eradication and long-term immune memory.

1. Cytotoxic T Lymphocytes (CTLs, CD8⁺ T cells) & NK Cells

Mechanisms of inducing apoptosis in tumor cells:

• Perforin/Granzyme Pathway

  • Perforin: forms transmembrane pores in the tumor cell’s plasma membrane.

  • Granzymes (mainly Granzyme B): serine proteases that enter via perforin pores.

    • Granzyme B cleaves and activates caspase-3 and caspase-7.

    • Granzyme B also cleaves Bid → tBid, which translocates to mitochondria, triggering BAX/BAK oligomerization and mitochondrial outer membrane permeabilization (MOMP) → release of cytochrome c.

    • Cytochrome c binds Apaf-1, forming the apoptosome → activation of caspase-9 → amplification of the caspase cascade.

• Death Receptor Pathway (extrinsic apoptosis)

  • CTLs and NK cells express Fas ligand (FasL) and TRAIL.

  • Binding to Fas (CD95) or TRAIL receptors on tumor cells recruits FADD/TRADD and procaspase-8 → DISC formation → activation of caspase-8 → downstream effector caspases (3/7) and Bid cleavage → apoptosis.

Outcome: Tumor cells undergo classical apoptosis → DNA fragmentation, membrane blebbing, release of apoptotic bodies.

2. Macrophages & Neutrophils (Innate Cleanup Crew)

• Phagocytosis of apoptotic corpses and debris

  • Exposed phosphatidylserine on dying tumor cells recognized by phagocytic receptors (e.g., TIM-4, BAI1).

  • Opsonization by IgG antibodies → Fcγ receptor-mediated phagocytosis.

  • Opsonization by C3b complement → CR1-mediated uptake.

• Effector molecules

  • ROS (reactive oxygen species) and RNS (reactive nitrogen species) damage residual tumor fragments.

  • Tumor necrosis factor-α (TNF-α) and other cytokines sustain local inflammation, recruiting additional effectors.

3. B Cells, Antibodies & Complement

• Antibody-Dependent Cellular Cytotoxicity (ADCC):

  • NK cells, macrophages, and neutrophils bind Fc regions of IgG (via FcγRIII/CD16).

  • Engagement triggers cytotoxic degranulation or ROS release → tumor cell death.

• Complement Activation (Classical Pathway):

  • IgM/IgG bound to tumor antigen → C1q recognition → complement cascade.

  • Membrane Attack Complex (MAC; C5b-9) forms pores in tumor cell membranes → osmotic lysis.

  • Complement fragments (C3a, C5a) serve as chemoattractants and inflammatory amplifiers.

4. Antigen Recycling & Immune Memory

• Dendritic Cells (DCs) scavenge tumor debris

  • Uptake via phagocytosis or macropinocytosis.

  • Processed peptides loaded onto MHC-I (cross-presentation) and MHC-II.

• Priming of adaptive immunity

  • Presentation to naïve CD8⁺ and CD4⁺ T cells in lymph nodes.

  • Reinforcement of tumor-specific effector T cells and induction of long-lived memory T cells.

  • B cells also receive T-cell help → long-lived plasma cells and memory B cells that maintain antibody titers.

5. The Crescendo: Integrated Outcome

1. Tumor cells die via apoptosis → clean, caspase-driven elimination.

Innate cells clear debris