Perforin–granzyme pathway

The perforin–granzyme pathway is a granule-mediated cytotoxic mechanism used by cytotoxic T lymphocytes and natural killer cells to kill virus-infected and transformed cells, relying on the pore-forming protein perforin to deliver serine protease granzymes (notably granzyme B) into target-cell cytosol, where granzymes trigger apoptosis through caspase activation and BID cleavage. Upon target recognition, cytotoxic lymphocytes form an immunological synapse and exocytose lytic granules containing perforin and granzymes; perforin facilitates granzyme entry via membrane pore formation and/or endocytic uptake with subsequent endosomal escape, a process essential for granzyme-dependent killing as shown in perforin-deficient models. While the canonical mechanism is perforin-dependent, receptor-mediated uptake of granzyme B and supramolecular attack particles have also been described, indicating additional or complementary delivery modes in specific contexts. Therapeutically, the pathway is both a target for inhibition in conditions like graft-versus-host disease and a chassis for engineered cell therapies or payload delivery, with efforts to exploit granzyme B’s potent pro-apoptotic activity against tumors.

Other names

Perforin/granzyme apoptosis pathwayGranzyme–perforin pathwayPerforin–granzyme cytotoxic pathway

Blocking the pathway can reduce CTL/NK-mediated apoptosis via inhibition of perforin/granzyme B entry or activity; Therapeutic delivery of granzyme B induces apoptosis in target tumor cells by activating caspases and BID after cytosolic entry (generally perforin-dependent)