Molecular warfare: Phagocyte killing Tumorcell

Phagocytes (like macrophages, neutrophils, and dendritic cells) can indeed kill tumor cells, but the mechanisms are quite different from how cytotoxic T cells or NK cells work. On the molecular level, here’s what happens:

1. Recognition of the Tumor Cell

• Opsonization: Tumor cells can be coated with:

• Antibodies (IgG)  Fcγ receptors on phagocytes bind them.

• Complement fragments (C3b, iC3b) Complement receptors (CR1, CR3, CR4) recognize them.

• DAMPs (damage-associated molecular patterns): Tumor cells release ATP, HMGB1, or surface calreticulin ? bind pattern recognition receptors (PRRs).

• “Eat-me” signals: Exposed phosphatidylserine or calreticulin on tumor cells promotes engulfment.

• Suppression of “don’t-eat-me” signals: Tumors often express CD47, which binds SIRPα on macrophages (“don’t eat me”). Blocking CD47–SIRPα enables phagocytosis.

2. Engulfment

• Actin cytoskeleton rearranges around the tumor cell (via Rac1, Cdc42, Arp2/3).

• The plasma membrane extends pseudopodia ? forms a phagosome around the tumor cell.

3. Phagosome Maturation

• The phagosome fuses with lysosomes, forming a phagolysosome.

• Key processes:

• Acidification (via vacuolar H-ATPase).

• Delivery of proteases (cathepsins, elastase).

• NADPH oxidase assembly at the membrane.

4. Killing Mechanisms inside the Phagolysosome

Phagocytes deploy several molecular weapons:

4.1a) Reactive Oxygen Species (ROS)

• NADPH oxidase (NOX2) generates superoxide .

• Superoxide dismutates hydrogen peroxide.

• In neutrophils, myeloperoxidase (MPO) converts H?O? + Cl? ? hypochlorous acid (HOCl), a potent cytotoxin.

• ROS damage DNA, lipids, and proteins tumor cell death.

4.2b) Reactive Nitrogen Species (RNS)

• Inducible nitric oxide synthase (iNOS) produces nitric oxide (NO).

• NO + superoxide peroxynitrite (ONOO?), which nitrates tyrosine residues and causes mitochondrial damage.

4.3c) Proteolytic Enzymes

• Lysosomal enzymes (cathepsins, serine proteases) digest tumor cell components.

• Elastase and matrix metalloproteinases can degrade tumor ECM and membranes.

4.4d) Iron & Nutrient Deprivation

• Macrophages can sequester iron via ferritin, limiting tumor cell metabolism.

5. Extracellular Mechanisms (if phagocytosis fails)

Sometimes tumor cells are too large to be fully engulfed phagocytes attack from outside:

• Antibody-dependent cellular phagocytosis (ADCP)  partial “nibbling” (trogocytosis).

• Extracellular ROS/RNS release damages tumor membranes.

• TNF-α, TRAIL, FasL secretion ? trigger apoptosis in tumor cells.

6. Immunogenic Consequences

• Phagocytosed tumor cells are degraded into peptides.

• Tumor antigens are presented on MHC-II (and sometimes cross-presented on MHC-I).

• This activates T helper cells and cytotoxic T cells, amplifying the anti-tumor immune response.

Summary in one line: A phagocyte kills tumor cells by opsonization-driven engulfment, phagolysosomal fusion, and deployment of ROS, RNS, proteases, and apoptosis-inducing cytokines, while also processing tumor antigens for adaptive immunity.