Perforin-1 and granzyme-mediated cytotoxic pathway

The perforin/granzyme-dependent cytotoxicity pathway is a principal mechanism by which cytotoxic T lymphocytes and natural killer cells eliminate virus-infected or malignant cells. Perforin-1 (a pore-forming protein) and granzymes (a family of serine proteases, with granzyme B being the best characterized) are co-released from cytotoxic granules at the immunological synapse formed with the target cell. Perforin creates pores in the target cell membrane, enabling the entry of granzymes, which then induce apoptosis through caspase activation and DNA fragmentation. This pathway is crucial for immune surveillance, and its dysregulation can predispose individuals to severe infections, cancer, or autoimmune disorders. Resistance in tumor cells may develop through the expression of granzyme inhibitors such as PI-9/SPI-6.

Other names

Perforin/granzyme pathwayGranule exocytosis pathwayCTL/NK cell cytotoxic pathway

Perforin forms pores in the target cell membrane, allowing granzymes entry to the cytosol where granzymes activate apoptotic pathways by cleaving intracellular substrates. Some drugs, such as concanamycin A, inhibit the acidification of cytotoxic granules, impeding perforin function. Tumors may express granzyme inhibitors (e.g., PI-9/SPI-6) as a resistance mechanism.